GB2485404A - Metal-complexed pyridyl-substituted tetrazole compounds and their use in treating cancer - Google Patents

Metal-complexed pyridyl-substituted tetrazole compounds and their use in treating cancer Download PDF

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GB2485404A
GB2485404A GB1019227.6A GB201019227A GB2485404A GB 2485404 A GB2485404 A GB 2485404A GB 201019227 A GB201019227 A GB 201019227A GB 2485404 A GB2485404 A GB 2485404A
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tetrazole
substituted
atom
optionally
group
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GB201019227D0 (en
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John Mcginley
Adrienne Fleming
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INST OF TECHNOLOGY TALLAGHT
National University of Ireland
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INST OF TECHNOLOGY TALLAGHT
National University of Ireland
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/02—Iron compounds
    • C07F15/025—Iron compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/04—Nickel compounds
    • C07F15/045—Nickel compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/06—Cobalt compounds
    • C07F15/065—Cobalt compounds without a metal-carbon linkage

Abstract

Metal-complexed pyridyl-substituted tetrazole compounds, pharmaceutical compositions comprising the compounds, and uses thereof in treating cancer. Specifically, compounds comprising at least one pharmaceutically acceptable metal atom; at least one pyridinyl-substituted tetrazole moiety attached to the at least one metal atom; and at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, attached to the at least one pyridinyl­substituted tetrazole moiety; or a pharmaceutically acceptable salt, hydrate, ester, or isomer thereof. Preferably, the metal is selected from iron, cobalt, copper and nickel. In another aspect, compounds comprising at least one pyridinyl-substituted tetrazole moiety; and at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, attached to the at least one pyridinyl-substituted tetrazole moiety; pharmaceutical compositions comprising the compounds, and uses thereof in treating cancer.

Description

Compounds
Field of the Invention
The present invention relates to metal-complexed pyridyl-substituted tetrazole compounds. Also disclosed are pharmaceutical compositions comprising the compounds, and uses thereof in treating cancer.
Background to the Invention
C/s-platin and carboplatin are widely used anti-cancer agents because they are effective against a wide range of cancers, including testicular, bladder and ovarian, for example. Unfortunately, many tumours, which were initially responsive to the platinum complexes, have developed resistance to these agents. Furthermore, these complexes also have serious toxicities, such as nephrotoxicity, nausea and vomiting, which significantly degrade a patient's quality of life.
One mode of action for an anti-cancer drug is through induced DNA damage. Complexes of transition metal ions; such as copper, manganese, and iron; have been shown to act in this way.
Numerous nitrogen donor ligands have been used in complexation studies of copper(ll) ions, including both cyclic and acyclic systems.
The development of "click" chemistry has resulted in an increase in tetrazole structures. The synthesis of functional compounds containing polyazole rings, particularly tetrazoles and their derivatives, offer certain practical applications. Tetrazole derivatives have found applications in therapeutics as antihypertensive agents, antibiotics, and drugs for AIDS treatment. They are also studied in the field of coordination chemistry. Both tetrazole and its derivatives, normally the 5-substituted derivatives, can act as both di-and poly-dentate ligands exhibiting several coordination modes. Mono 1-and 2-substituted tetrazoles are often used for the construction of coordination networks.
Summary of the Invention
According to a first aspect of the present invention there is provided a compound comprising: a) at least one pharmaceutically acceptable metal atom; b) at least one pyridinyl-substituted tetrazole moiety attached to the at least one metal atom; and c) at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, attached to the at least one pyridinyl-or a pharmaceutically acceptable salt, hydrate, ester, or isomer thereof.
By "substituted" is meant a chemical compound, wherein at least one other atom, or a polyatomic molecule replaces at least one hydrogen atom of the compound.
By the term "linear" is meant a molecule comprising at least two atoms, any of which can be the same or different, wherein each atom of the molecule is bonded to an adjacent atom in a substantially straight series. For example, each atom may be a carbon atom, and each atom can be bonded to an adjacent carbon atom by a single-, double-, triple-, or higher order-bond. Non-limiting examples include n-propane, n-butane, and n-pentane.
By the term "branched" is meant a molecule comprising at least three atoms, any of which can be the same or different, bonded in a substantially straight series, wherein the molecule further comprises at least one other atom, which is not bonded to either of the terminal atoms of the substantially straight series. For example, each atom may be a carbon atom, and each atom can be bonded to an adjacent atom by a single-, double-, triple-, or higher order-bond. Non-limiting examples include isopentane (2-methylbutane), and neopentane (2,2-dimethylpropane).
Optionally, the at least one metal atom is a pharmaceutically acceptable metal selected from any of Group 8, Group 9, Group 10, Group 11, and Group 12, of the periodic table of elements. Further optionally, the at least one metal atom is a pharmaceutically acceptable metal selected from Group 10 or Group 11 of the periodic table of elements. Preferably, the at least one metal atom is a pharmaceutically acceptable metal selected from Group 11 of the periodic table of elements.
Optionally, the at least one metal atom is selected from iron, cobalt, nickel, zinc, silver, platinum, and copper. Preferably, the at least one metal atom is copper.
Optionally, the compound further comprises at least one anion ligand, each anion ligand being associated with the at least one metal atom, and each anion ligand being independently selected from halides, pseudohalides, perchlorate, sulphate, acetate, nitrate, and a water molecule (H20).
Optionally, the halide is selected from fluoride, chloride, bromide, iodide, and astatide; further optionally fluoride, chloride, bromide, and iodide; still further optionally fluoride, chloride, and bromide. Preferably, the halide is chloride.
Optionally, the pseudohalide is selected from a cyanide group (CEN), cyanate group ([OGN]], or thiocyanate group ([SCNI). Preferably, the pseudohalide is a cyanide group (CEN).
Optionally, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to any atom of the tetrazole component. Preferably, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the carbon atom of the tetrazole component.
Optionally, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the tetrazole component at any atom of the pyridine component. Preferably, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the tetrazole component at any carbon atom of the pyridine component. Further preferably, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the tetrazole component at the position 2 carbon atom of the pyridine component.
Optionally, the at least one metal atom is attached to any atom of the at least one pyridinyl-substituted tetrazole moiety. Preferably, the at least one metal atom is attached to any nitrogen atom of the at least one pyridinyl-substituted tetrazole moiety. Further preferably, the at least one metal atom is attached to at least two nitrogen atoms of the at least one pyridinyl-substituted tetrazole moiety. Still further preferably, the at least one metal atom is independently attached to the nitrogen atom of the pyridine component of the at least one pyridinyl-substituted tetrazole moiety, and to a nitrogen atom of the tetrazole component.
Preferably, the at least one metal atom is independently attached to the nitrogen atom of the pyridine component of the at least one pyridinyl-substituted tetrazole moiety, and to the nitrogen atom at position 4 of the tetrazole component.
Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to any atom of the at least one pyridinyl-substituted tetrazole moiety. Preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to any atom of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety. Further preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to any nitrogen atom of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety.
Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to a nitrogen atom selected from the nitrogen atom at position 1, the nitrogen atom at position 2, the nitrogen atom at position 3, and the nitrogen atom at position 4, of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety. Preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to the nitrogen atom at position 2 of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety.
Alternatively, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to any atom of the pyridine component of the at least one pyridinyl-substituted tetrazole moiety. Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to any carbon atom of the pyridine component of the at least one pyridinyl-substituted tetrazole moiety.
Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to a carbon atom selected from the carbon atom at position 3, the carbon atom at position 4, the carbon atom at position 5, and the carbon atom at position 6, of the pyridine component of the at least one pyridinyl-substituted tetrazole moiety.
Preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to a carbon atom selected from the carbon atom at position 4, the carbon atom at position 5, and the carbon atom at position 6, of the pyridine component of the at least one pyridinyl-substituted tetrazole moiety.
Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is a C 1-012; optionally a 03-012; alkyl, alkenyl, or alkynyl group. Preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is a C6 alkyl, alkenyl, or alkynyl group.
Optionally, the at least one alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is an unsubsitituted alkyl, alkenyl, or alkynyl group.
Preferably, the at least one alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is a subsitituted alkyl, alkenyl, or alkynyl group. Further preferably, the at least one alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is a Optionally, the subsitituted alkyl, alkenyl, or alkynyl group is substituted, at any position, by any one or more of: a) a halogen; b) anestergroup; c) a carboxyl group; and d) a hydroxyl group.
Optionally, the halogen is selected from fluorine, chlorine, bromine, and iodine; further optionally fluorine, chlorine, and bromine. Preferably, the halogen is bromine.
Optionally, the ester group is an alkyl ester group. By "alkyl ester" group is meant a functional group comprising a carbon atom attached to a first oxygen atom via a double bond, the carbon atom attached to a second oxygen atom via a single bond, the second oxygen atom attached to at least one substituted or unsubstituted alkyl group, which can be branched or unbranched, linear or cyclic.
S
Optionally, the ester group is an ethyl ester group, which comprises a functional group comprising a carbon atom attached to a first oxygen atom via a double bond, the carbon atom attached to a second oxygen atom via a single bond, the second oxygen atom attached to an ethyl group.
Optionally, the subsitituted alkyl, alkenyl, or alkynyl group is substituted at the terminal carbon atom.
Optionally, the alkyl group is a Cl-C 12 alkyl group, which can be branched or unbranched, linear or cyclic, and which is substituted. Preferably, the alkyl group is a linear C3-C12 alkyl group, and which is substituted. Further preferably, the alkyl group is an unbranched linear C3-C12 alkyl group, and which is substituted. Non-limiting examples include an n-propyl, n-butyl, n-hexyl, n-octyl, and n-decyl group.
Preferably, the alkyl group is a C6 alkyl group, which can be branched or unbranched, linear or cyclic and which is substituted. Preferably, the alkyl group is a linear C6 alkyl group and which is substituted. Further preferably, the alkyl group is an unbranched linear C6 alkyl group and which is Optionally, the compound has the general formula (I): L\ /N.. I N'-N R (I) wherein; M is a pharmaceutically acceptable metal atom; L is an anion ligand, wherein each anion ligand being independently selected from halides, pseudohalides, perchlorate, sulphate, acetate, nitrate, and a water molecule (HO); R is an alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic; and X is selected from: a) a halogen; b) anestergroup; c) a carboxyl group; d) a hydroxyl group; and e) a hydrogen atom.
or a pharmaceutically acceptable salt, hydrate, ester, or isomer thereof.
Optionally or additionally, the compound has the general formula (IA): / N'LN \
V I
N
(IA) X ix Optionally or additionally, the compound has the general formula (IB): Xe' R N*-N Nz (IB) X A Optionally, M is a pharmaceutically acceptable metal atom selected from any of Group 8, Group 9, Group 10, Group 11, and Group 12, of the periodic table of elements. Further optionally, M is selected from Group 10 or Group 11 of the periodic table of elements. Preferably, M is selected from Group 11 of the periodic table of elements.
Optionally, M is selected from iron, cobalt, nickel, zinc, silver, platinum, and copper. Preferably, M is copper.
Optionally, the halide is selected from fluoride, chloride, bromide, iodide, and astatide; further optionally fluoride, chloride, bromide, and iodide; still further optionally fluoride, chloride, and bromide. Preferably, the halide is chloride.
Optionally, the pseudohalide is selected from a cyanide group (05N), cyanate group ([OCN]), or thiocyanate group ([SCN]]. Preferably, the pseudohalide is a cyanide group (CEN).
Optionally, the halogen is selected from fluorine, chlorine, bromine, and iodine; further optionally fluorine, chlorine, and bromine. Preferably, the halogen is bromine.
Optionally, R is an alkyl group, which can be branched or unbranched, linear or cyclic. Optionally, R is a 01-012 alkyl group, which can be branched or unbranched, linear or cyclic. Preferably, R is a linear 03-C 12 alkyl group. Further preferably, R is an unbranched linear 03-012 alkyl group.
Preferably, R is a 06 alkyl group, which can be branched or unbranched, linear or cyclic. Preferably, R is a linear 06 alkyl group. Further preferably, R is an unbranched linear 06 alkyl group.
Optionally, X is an alkyl ester. Further optionally, X is an ethyl ester.
For the purposes of this specification, in the case of a polyatomic molecule represented by text, a single bond extending between any two atoms is represented by a solid dashed line (-), a double bond extending between any two atoms is represented by a double solid dashed line (=), and a triple bond extending between any two atoms is represented by a triple solid dashed line (E), unless otherwise stated.
It is understood that, in the case of the compounds of the first aspect of the present invention, each compound comprises at least one anion ligand, each anion ligand being associated with the at least one metal atom. The number of anion ligands associated with the at least one metal atom is dependent on the valence of the metal atom. For example, iron and silver, each have a valence of three; cobalt has a valence of four; nickel, copper, and zinc, each have a valence of two; platinum has a valence of six. Accordingly, each compound as described or illustrated herein may comprise further anion ligands associated with the at least one metal atom, which are not exclusively depicted in the general structures described.
Optionally, the compound has the general formula (IA); M is cobalt; L is a thiocyanate group; R is a 06 aIkyl group, attached to the nitrogen atom at position 1 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IA); M is cobalt; L is a thiocyanate group; R is a 06 alkyl group, attached to the nitrogen atom at position 2 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IA); M is iron; L is a water molecule; R is a 06 alkyl group, attached to the nitrogen atom at position I of the tetrazole component; and X is bromine.
S
Optionally, the compound has the general formula (IB); M is copper; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 1 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IB); M is copper; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 2 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IB); M is cobalt; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position I of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IB); M is nickel; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 1 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IB); M is cobalt; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 2 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IB); M is nickel; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 2 of the tetrazole component; and X is bromine.
Optionally, the compound has the general formula (IB); M is copper; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 1 of the tetrazole component; and X is hydrogen.
Optionally, the compound has the general formula (IB); M is copper; L is chloride; R is a 06 alkyl group, attached to the nitrogen atom at position 2 of the tetrazole component; and X is hydrogen.
According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the first aspect of the present invention.
Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
Optionally, the excipient is a polar excipient, such as an alcohol, or aqueous solution thereof.
Preferably, the alcohol is selected from methanol and ethanol. Further preferably, the alcohol is methanol.
Alternatively, the excipient is at least one non-ionic surfactant, or a mixture thereof. Further optionally, the non-ionic surfactant is selected from Polysorbate 80 (Tween 80), polyethoxylated castor oil, polyethylene glycol, polyethylene glycol-400, polyethylenglycol 660-1 2-hydroxystearate, and 2-Pyrrolidone.
According to a third aspect of the present invention, there is provided a compound according to the first aspect of the present invention, or a pharmaceutical composition according to the second aspect of the present invention, for use in treating cancer.
Optionally, the cancer is a solid tumour cancer.
Optionally, the cancer is selected from renal cancer, liver cancer, prostate cancer, and breast cancer.
According to a fourth aspect of the present invention there is provided a compound comprising at least one pyridinyl-substituted tetrazole moiety attached to the at least one metal atom; and at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, attached to the at least one pyridinyl-substituted tetrazole moiety; or a pharmaceutically acceptable salt, hydrate, ester, or isomer thereof.
Optionally, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to any atom of the tetrazole component. Preferably, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the carbon atom of the tetrazole component.
Optionally, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the tetrazole component at any atom of the pyridine component. Preferably, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the tetrazole component at any carbon atom of the pyridine component. Further preferably, the pyridine component of the at least one pyridinyl-substituted tetrazole moiety is attached to the tetrazole component at the position 2 carbon atom of the pyridine component.
Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to a nitrogen atom selected from the nitrogen atom at position 1, the nitrogen atom at position 2, the nitrogen atom at position 3, and the nitrogen atom at position 4, of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety.
Preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to the nitrogen atom at position 2 of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety.
Alternatively, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is attached to the nitrogen atom at position 3 of the tetrazole component of the at least one pyridinyl-substituted tetrazole moiety.
Optionally, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is a C1-C12; optionally a C3-C12; alkyl, alkenyl, or alkynyl group. Preferably, the at least one substituted or unsubstituted alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is a C6 alkyl, alkenyl, or alkynyl group.
Optionally, the at least one alkyl, alkenyl, or alkynyl group, which can be branched or unbranched, linear or cyclic, is an unsubsitituted alkyl, alkenyl, or alkynyl group.
According to a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the fourth aspect of the present invention.
According to a sixth aspect of the present invention, there is provided a compound according to the fourth aspect of the present invention, or a pharmaceutical composition according to the fifth aspect of the present invention, for use in treating cancer.
Brief Description of the Drawings
Embodiments of the present invention will be described, by way of non-limiting example, and with reference to the accompanying drawings, in which: Figure 1 depicts the molecular structure of JGI with displacement ellipsoids at the 50% probability level for non-H atoms; Figure 2 depicts the molecular structure of JG2 with displacement ellipsoids at the 50% probability level for non-H atoms; Figure 3 depicts the molecular structure of JG3; Figure 4 depicts the molecular structure of JG6; Figure 5 is a partial packing diagram for JG6, to illustrate SBr interactions; Figure 6 depicts the molecular structure of JG7; and Figure 7 is a partial packing diagram for JG7, to illustrate H-bonding interactions.
Examples
Example I: Ligand syntheses and characterisation The synthesis of 5-(2-pyridyl)tetrazole (LI) and its subsequent reaction with 1,6-dibromohexane to give the isomers 2-(6"-bromohexyl-(l-tetrazol-S-yl)pyridine (L2) and 2-(6"-bromohexyl-(2-tetrazol-5-yl)pyridine (L3) were carried out, as shown in Scheme 1, in a manner similar to that described by H. Gallardo, R. Magnago, A. J. Bortoluzzi, Liquid Gryst., 2001, 28, 1343. The reaction of sodium azide with 2-cyanopyridine in the presence of ammonium chloride and lithium chloride in dry dimethylformamide (DMF) yielded LI as brown needles, on recrystallisation from ethanol. The 13C NMR and IR spectra of the needles confirmed the presence of the tetrazole ring with the presence of a signal at 154.9 ppm in the 130 NMR spectrum indicating the formation of a 1,5-disubstituted tetrazole and the absence of a signal at 2220 cm in the IR spectrum due to an azide band. The 1H NMR spectrum of LI, obtained in CD3OD, showed the expected signals for the pyridine ring, while the NH proton on the tetrazole appeared as a broad signal at 3.9 ppm.
The reaction of LI with I,6-dibromohexane in 2-butanone with potassium carbonate as base gave a mixture of products L2 and L3. Column chromatography separated the products from the reactants.
Both L2 and L3 are low melting, waxy solids. The isomeric 1-N or 2-N derivatives are readily distinguishable by their 130 NMR spectra with the 130 NMR chemical shift of the tetrazole carbon atom appearing at Ca. 154.0 and 164.0 ppm in the 1,5-and 2,5-disubstituted tetrazoles, respectively.
The 1-N isomer (L2) gave a signal at 151.4 ppm, while the 2-N isomer (L3) gave a signal at 164.7 ppm. The 1H NMR spectra of both L2 and L3 show four signals for the pyridyl protons, a triplet for methylene group beside the bromine, a triplet for the methylene group beside the tetrazole and three other signals for the remaining methylene groups of the bromohexyl chain. The signals for the methylene protons beside the tetrazole vary from 5.00 ppm for L2 to 4.73 ppm for L3 on going from the 1-N isomer to the 2-N isomer.
Example 2: Metal Complexation Reactions Three metal salts (CuCI2.2H20; Co(SCN)2; and Fe(C104)2.H20) were reacted with L2 and L3, respectively, in methanol at reflux temperature under an inert atmosphere for two hours. All reactions were carried out using a 1:1 metal:ligand stoichiometry (see Schemes 2 & 3). The resulting highly coloured solutions were then allowed to stand for several days. After this time, crystalline materials were obtained from several of the reactions, with powders being obtained in the remaining cases.
Elemental analyses on all the metal complexes obtained showed that the copper complexes (JGI & JG2) have a 1:1 metal:ligand composition while both the cobalt complexes (JG3 & JG6)and the iron complexes (JG7 & JG8) had a 1:2 metal:ligand composition.
R \\ JG1
CI
R / \\ H
R
N -N /N N ii) / G4 \
R
R /N \\ H
N N \\ /
R
Scheme 2. Reaction conditions: i) CuCI2.2H20, MeOH, LI, 2 hr; ii) Co(SCN)2, MeOH, A, 2 hr; i) Fe(C104)2.xH2O, MeOH, A, 2 hr.
R / JG2 R
ii) 2+ 111) N_N R _ / / NN 2+ 1/ \ /N N'yK!=) \/ I" JG8 Scheme 3. Reaction conditions: i) CuCI2.2H20, MeOH, A, 2 hr; ii) Co(SCN)2, MeOH, A, 2 hr; i) Fe(Cl04)2.xH2O, MeOH, A, 2 hr.
The magnetic moments of all six complexes were measured. The copper complexes JGI and JG2 have magnetic moment values of 2.6 and 3.2 B.M., respectively, which indicate the presence of a copper(ll) species. Both cobalt complexes (JG3 and JG6) have magnetic moments of 4.5 and 3.65 B.M., which are consistent with the presence of high-spin cobalt(ll) species. The magnetic moments for the iron complexes (JG7 and JG8) were 4.7 and 5.0 B.M., respectively, which indicated the presence of a high-spin iron(ll) species in both complexes. This is consistent with the findings of Henderson eta!. who reported that several manganese(ll) complexes of L all contained high-spin manganese(ll) species.
Example 3: X-Ray Analyses of Copper complexes Dark green crystals of JGI and JG2, suitable for an X-ray diffraction study, were recrystallised from methanol and ethanol solutions of CuCI2.H20 with JG4 and JG5, respectively. Crystallographic data for all structures are presented in Table 1.
Table 1. Crystallographic Data for JGI, JG2, JG3, JG6 and JG7 JGI JG2 JG3 JG6 JG7 Formul C24H32 C24H32 C26H32 C26H32 C24H36 a Br2CI4 Br2CI4 Br2Co Br2Co Br2CI2 Cu2N10 Cu2N10 N12S2 N12S2 FeN10 Weight 889.30 889.30 795.51 795.51 911.20 Cryst Triclini Triclini Triclini Triclini Monoc syst c c c c linic Space F-i P-i P-I P-i P2(1)! gp c a/A 9.2946 9.5645 8.7827 8.2324 9.8682 (5) (17) (4) (15) (11) b/A 9.4441 12.213 12.111 12.863 11.706 (7) (2) 2(6) (2) 1(12) c/A 10.613 14.688 16.096 15.951 15.278 2(7) (3) 3(6) (3) 4(16) ct!° 76.945 92.214 83.204 99.917 90 (2) (3) (2) (3) 80.052 107.25 83.219 93.901 92.999 (2) 6(2) (2) (3) (2) 66.114 93.937 74.195 90.270 90 (2) (2) (2) (3) V/A3 826.35 1631.5 1629.2 1659.8 1762.5 (9) (5) 3(13) (5) (3) Z 1 2 2 2 2 Densit 1.787 1.810 1.622 1.592 1.717 y F(000) 442 884 802 802 920 GOF 1.092 1.033 1.035 1.052 1.045 FinaIR 0.0264 0.0659 0.0411 0.0811 0.0470 0.0725 0.1836 0.1020 0.2065 0.1041 R(all 0.0303 0.1170 0.0567 0.1642 0.0696 data) , , 0.0741 0.2165 0.1075 0.2515 0.1147 Both structures confirmed the presence of the pendant bromohexyl arm at the 1-N and 2-N position of the tetrazole ring, respectively (see Figures 1 and 2). In JGI, the two halves of the dimer unit are related by inversion, with the inversion centre being at the midpoint between the two copper atoms.
In JG2, one of the hexyl chains is quite severely disordered and was refined over three orientations with occupancies of 40%, 40% and 20%. This also accounts for the difference between both sides of the molecule. Both JGI and JG2 consist of dichloro-bridged dimeric {Cu(JG2)(p-Cl)Cl}2 units. The coordination geometry about each copper(ll) atom in both JGI and JG2 contains one pyridine nitrogen atom, one tetrazole atom and three chlorine atoms, two of which are bridging the two copper atoms in the structure. Selected bond distances and angles for JGI and JG2 are listed in Tables 2 and 3, respectively.
Table 2. Selected bond lengths (A) and angles (°) for JGI Cu(1)-N(4) 1.987(2) Cu(1)-N(5) 2.088(2) Cu(1)-Cl(2) 2.2257(8) Cu(1)-Cl(1) 2.2553(7) Cu(1)-Cl(1)#1 2.6392(8) Br(1)-C(12) 1.952(3) N(4)-Cu(1)-N(5) 78.19(9) N(4)-Cu( I)-Cl(2) 92.38(7) N(5)-Cu( 1)-Cl(2) 160.64(7) N(4)-Cu( I)-Cl( 1) 1 72.29(7) N(5)-Cu(1)-Cl(1) 94.28(6) Cl(2)-Cu( 1)-Cl( 1) 94.32(3) N(4)-Cu(1)-Cl(1)#1 91.82(7) N(5)-Cu(1)-Cl(1)#1 91.20(6) Cl(2)-Cu(1)-Cl(1)#1 106.12(3) Cl( 1)-Cu(1)-Cl(1)#1 89.97(2) Cu(1)-Cl(1)-Cu(1)#1 90.03(2) Table 3. Selected bond lengths (A) and angles (°) for JG2 Cu(1)-N(12) 2.012(6) Cu(1)-N(1 1) 2.085(6) Cu(1)-Cl(3) 2.235(2) Cu(1)-Cl(2) 2.2637(19) Cu(1)-Cl(1) 2.716(2) Cu(2)-N(32) 2.013(6) Cu(2)-N(3 1) 2.090(6) Cu(2)-Cl(4) 2.229(2) Cu(2)-Cl(1) 2.3178(18) Cu(2)-Cl(2) 2.671(2) C(22)-Br(1) 1.910(9) C(42)-Br(2) 1.902(18) C(42#)-Br(2#) 1.897(18) C(42)-Br(2) 1.90(2) N(12)-Cu(1)-N(1 1) 78.5(2) N(12)-Gu(1)-Cl(3) 91.79(19) N(1 1)-Cu(1)-Cl(3) 165.0(2) N(12)-Cu(1)-Cl(2) 167.9(2) N(1 1)-Cu(1)-Cl(2) 93.66(18) Cl(3)-Cu(1)-Cl(2) 93.87(8) N(12)-Cu(1)-Cl(1) 97.0(2) N(1 I)-Cu(1)-Cl(1) 91.24(19) Cl(3)-Cu(1)-Cl(1) 101.41(8) Cl(2)-Cu(1)-Cl(1) 92.36(7) N(32)-Cu(2)-N(31) 78.5(2) N(32)-Cu(2)-Cl(4) 90.89(18) N(31)-Cu(2)-CI(4) 162.39(19) N(32)-Cu(2)-Cl(1) 169.71(19) N(31)-Cu(2)-Cl( 1) 94.41(1 7) Cl(4)-Cu(2)-Cl(1) 94.10(7) N(32)-Cu(2)-Cl(2) 95.09(19) N(31)-Cu(2)-Cl(2) 90.10(19) Cl(4)-Cu(2)-Cl(2) 104.93(8) Cl( I)-Cu(2)-Cl(2) 92.30(7) Cu(2)-Cl(1)-Cu( 1) 86.57(6) Cu(1)-Cl(2)-Cu(2) 88.75(7) The geometry for the copper centre in JGI is distorted square pyramidal with a rvalue of 0.19. The structural parameter r describes the relative amount of trigonality with T = 0 for ideal square pyramidal and r = I for ideal trigonal bipyramidal. The geometry for both copper centres in JG2 are slightly distorted square pyramidal with T values of 0.05 for Cu(1) and 0.12 for Cu(2), respectively.
Each pyridyl-tetrazole ligand in JGI and JG2 binds to the copper atom through one tetrazole- nitrogen at the 1-N site of the tetrazole ring and through the pyridyl nitrogen atom to generate a five-membered ring. The tetrazole ring is coplanar with the pyridyl ring. Due to its inherent inversion symmetry, the four-membered Cu2CI2 rings in both JGI and JG2 are planar. The copper(ll)-Cl bond distances are in line with the metric parameters of other dichloro-bridged dimers. The Cu-Cl(apical) bond distances are longer by -0.35 A than the Cu-Cl(equatorial) bond distances in both JGI and JG2, as shown in Table 1. The significance of the point of attachment of the bromohexyl arm to the tetrazole ring manifests itself in the crystal packing of both structures. In JGI, the bromohexyl arm is attached to the 1-N nitrogen atom of the ring while in JG2 it is attached to the 2-N nitrogen atom.
However, in JGI, the two bromohexyl arms orient themselves above and below the central Cu2CI2 core, pointing away from each other, whereas in JG2, both arms point in the same direction. This difference in orientation is probably due to packing effects, as there are several interactions between the pyridyl-tetrazole ligands of various molecules.
Example 4: X-Ray Analyses of Cobalt complexes Crystals of both cobalt(ll) complexes, JG3 and JG6, were structurally characterised. Rust-coloured crystals of JG3 were obtained from a methanol solution while green crystals of JG6 were recrystallised from ethanol. Both structures confirmed the presence of the pendant bromohexyl arm at the 1-N and 2-N position of the tetrazole ring, respectively, and also the 1:2 metal:Iigand composition of the complexes (see Figures 3 and 4). The asymmetric units of JG3 and JG6 consist of independent half-molecules, each lying on a centre of symmetry. Selected bond distances and angles for JG3 and JG6 are listed in Tables 4 and 5, respectively.
Table 4. Selected bond lengths (A) and angles (°) for JG3 Co(1)-N(4) 2.142(3) Co(1)-N(4A) 2.122(3) Co(1)-N(5) 2.139(3) Co(1)-N(SA) 2.144(3) Co(1)-N(6) 2.039(3) Co(1)-N(6A) 2.082(3) N(6)-Co(1)-178.22(13) N(6)-Co(1)-94.33(12) N(6A) N(4A) Table 5. Selected bond lengths (A) and angles (°) for JG6 Co(1)-N(30) 2.080(7) Co(2)-N(40) 2.061(9) Co(1)-N(2) 2.142(6) Co(2)-N(7) 2.137(7) Co(1)-N(1) 2.158(6) Co(2)-N(6) 2.156(6) N(30)-Co(1)-N(2) 92.4(3) N(40)-Co(2)-N(7) 88.6(3) N(30)#1 -Co(1)-N(2) 87.6(3) N(40)#2-Co(2)-N(7) 91.4(3) N(30)-Co(1)-N(1) 92.1(2) N(40)-Co(2)-N(6)#2 87.4(3) N(30)#1 -00(1)-N(1) 87.9(2) N(40)#2-Co(2)-N(6)#2 92.6(3) N(2)-Co(1)-N(1) 76.7(2) N(7)-Co(2)-N(6)#2 102.8(2) N(2)#1 -00(1)-N(1) 103.3(2) N(7)-Co(2)-N(6) 77.2(2) In both JG3 and JG6, each cobalt atom occupies an octahedral geometry with the equatorial plane consisting of two pyridyl-tetrazole ligands while the thiocyanate ligands are in the axial positions.
Each pyridyl-tetrazole ligand chelates to the cobalt through one tetrazole nitrogen atom at the 1-N site and through the pyridyl nitrogen atom. As in the cases of JGI and JG2, the tetrazole rings are coplanar with the pyridine rings in JG3 and JG6. In JG6, the two independent alkyl chains are both disordered. As a result, the molecule containing Col was modelled with 50% occupancy of the two overlapping sites and that containing Co2 was modelled with a 70:30% occupancy. This disorder has resulted in a poor refinement and consequently a high R factor. In the packing diagram of JG6, eight molecules containing Col occupy the corners of the cuboid, while two of the molecules containing 0o2 occupy the centre of two opposing faces. As a result of this, there is an interaction of 3.441 A between the sulphur atom of one thiocyanate group and the bromine of a bromohexyl arm of a second molecule (see Figure 5).
Example 5: X-Ray Analysis of Iron complex Brown crystals were obtained from the reaction between iron(ll) perchlorate and JG5, and the molecular structure, with associated disorder, is shown in Figure 6.
The cation is centrosymmetric and there is disorder in the alkyl chain, which is modelled as 50% occupancy of two sets of positions. The perchlorate anion is also disordered and is modelled with 50% occupancy of two overlapping sites. The iron(Il) centre adopts a slightly distorted octahedral coordination geometry with the pyridyl-tetrazole ligand JG5, bonding through the pyridyl nitrogen atom and the tetrazole 1-N nitrogen, occupying the equatorial plane and a water molecule occupying the axial positions. As in the cases of JOl, JG2, JG3 and JG6, the tetrazole ring is coplanar with the pyridine ring. Selected bond lengths and angles for JG7 are given in Table 6. Each perchlorate anion is involved in two hydrogen-bonding interactions to two different water molecules, which results in the layered architecture shown in Figure 7.
Table 6. Selected bond lengths (A) and angles (°) for JG7 Fe(1)-Q(1 W) 2.122(3) Fe(1)-N(1) 2.199(3) Fe(1)-N(2) 2.141(3) C(12)-Br(1) 1.947(4) O(1W)-Fe(1)-N(2) 88.10(11) O(IW)-Fe(1)-N(2)#1 91.90(11) O(1W)#1-Fe(1)-N(1) 89.46(10) O(IW)-Fe(1)-N(1) 90.54(10) N(2)-Fe-N(1) 75.03(11) N(2)#1 -Fe(1)-N(1) 104.97(11)
S
The X-ray structures of several metal(ll) complexes of S-(2-pyridyl)tetrazole derivatives, containing a 6-bromohexyl pendant arm at either the 1-N (JG4) or 2-N (JG5) position of the tetrazole ring, have been studied. In all cases, the 5-(2-pyridyl)tetrazole ligand coordinates in a bidentate fashion through the pyridine nitrogen atom and the 1-N nitrogen of the tetrazole ring to form a stable five-membered ring with the metal ion. The coordination geometries about the two copper(ll) complexes (JGI and JG2) are slightly distorted square-pyramidal, due mainly to the formation of a dimeric Cu2CI2 core.
The coordination geometry at the metal centres in the other three structures (JG 3, JG6, and JG7) can be described as slightly distorted octahedral, with two S-(2-pyridyl)tetrazole ligands occupying the equatorial plane in all cases. The axial positions are occupied by the two thiocyanate anions in the cobalt cases, while they are occupied by two water molecules in the case of the iron(ll) complex.
These water molecules are further involved in hydrogen bonding to the perchlorate anions to give a layered structure. Interestingly, there are no interactions, in any of the structures, between the metal ion centre and the bromine atom at the ends of the pendant arms.
Example 6: Synthesis of 2-(2H-tetrazol-5-yl)pyridine (L) A suspension of 2-cyanopyridine (40 mmol), sodium azide (90 mmol), ammonium chloride (90 mmol) and lithium chloride (280 mmol) in anhydrous dimethylformamide (40 ml) was stirred for 10 hours at °C. After this time, the solution was cooled and the insoluble salts were removed by filtration.
The solvent was then evaporated under reduced pressure and the residue was dissolved in deionised water (200m1) and acidified with concentrated HCI (3m1), to initiate precipitation. The product was removed by filtration, washed with water (3 x 40 ml) and dried to give a brown solid.
This was recrystallised from hot ethanol to afford L as brown needles.
Example 7: Synthesis of 2-(6"-bromohexyl-(1-tetrazol-5-yl)pyridine (JG4) and 2-(6"-bromohexyl-(2-tetrazol-5-yl)pyridine (JG5) To L (6.8 mmol) dissolved in 2-butanone (30 ml) was added potassium carbonate (68 mmol). The resulting solution was refluxed for 30 minutes and to the hot solution was added 1,6-dibromohexane (24 mmol). The reaction mixture was then stirred at reflux temperature for a further 24 h. After cooling, the solvent was removed under reduced pressure to afford an oil, which was purified by column chromatography on silica gel (initially at a ratio of petroleum ether:ethyl acetate 80:20, followed by the ratio of 60:40). This gave the products JG4 and JG5. Br
N( jg
N-N
2-( 1 -(6-bromohexyl)-1 H-tetrazol-5-yl)pyridine Br jg
N
2-(2-(6-bromohexyl)-2H-tetrazol-5-yl)pyridine The appropriate 5-(2-pyridyl)-tetrazole ligand, JG4 or JG5 (1.36 mmol), was dissolved in methanol (30 mL) and was added to a solution of the appropriate metal salt (1.36 mmol) in methanol (25 mL).
The resulting highly-coloured solution was then heated to reflux for 2 h before being allowed to stand at room temperature for several days. o,J zz z z 0 - z,z -/Br jgl zcucI
CI
ciI,,.,ci Cu N-N 1 N \ j BrJ) Br 0N\ 7 jg 2 most active
N
cuc-CI
CI
,,,ci qu NN' \ \ "N
H Br! / N
N\\ ii / C24HBrC14Co2N10 NNCO / / .. \\
Exact Mass: 875.85963 ci CI / q N Mo!. Wt: 880.06428 JG 16 Brw / I N N/ / C24H32Br2CLN10Ni2 \\ _N__Nj_C.. / Exact Mass: 873.86392 N x \\ MoL Wt: 879.58468 CI CI / I N JG 17 C,4H1,Br2C14Co2N10 Exact Mass: 875.8 5963 Mo!. Wt.: 880.06428 JG 18 / ci N-Co N Br "N N Br ci / QAN, C24H32Br2C!4N10Ni2 Mo!.Wt.: 879.58468 Exact Mass: 873.86392 N,,JL) JG19 / NN{c Br NiN N ci / (y#LN/ Example 8: Synthesis of 2-(1 -hexyl-1 H-tetrazol-5-yl)-pyridine (JGI 2) and 2-(2-hexyl-2H-tetrazol-5-yl)-pyridine (JGI 3) To L (6.8 mmol) dissolved in 2-butanone (30 ml) was added potassium carbonate (68 mmol). The resulting solution was refluxed for 30 minutes and to the hot solution was added 1-bromohexane (24 mmol). The reaction mixture was then stirred at reflux temperature for a further 24 h. After cooling, the solvent was removed under reduced pressure to afford an oil, which was purified by column chromatography on silica gel (initially at a ratio of petroleum ether:ethyl acetate 80:20, followed by the ratio of 60:40). This gave the products JGI2 and JGI3.
JG13.1 12
I
C12H17N5 C12H17NS Exact Mass: 231.1484 Exact Mass: 231.1484 Mol. Wt: 231.29688 MoL Wt: 23 1.29688 The appropriate 5-(2-pyridyl)-tetrazole ligand, JGI2 or JGI3 (1.36 mmol), was dissolved in methanol (30 mL) and was added to a solution of the appropriate metal salt (1.36 mmol) in methanol (25 mL).
The resulting highly-coloured solution was then heated to reflux for 2 h before being allowed to stand at room temperature for several days. JG 14 /
N
NNCU / / \ Cu--_....NJ+_N \\ CI / N
N N
C24H34C14Cu2N10 Exact Mass: 728+0314 Mo!. Wt.: 731.49776 Ny!=(D JG1S
N CIC N
\ C1r-.N CI / N C24H34C!4Cu2N10 Exact Mass: 728+0314 Mol+Wt: 731+49776 Example 9: Cytotoxicity Studies Each test agent was dissolved in methanol or ethanol, diluted in culture media and used to treat A- 498 cells at various drug concentrations for a period of 96 hr, prior to MTT assay (see also Figure 8).
Table 7: All compounds were tested on A498 renal adenocarcinoma cell lines. Cytotoxicity was determined by MTT conversion assay following 96 hr treatment Compound ICSO pM ±S.E.M. ICSO pM ±S.E.M.
(solubilised in 0.5% (solubilised in 0.5% MeOH) EtOH) JG1 29.5±1.1 N/D JG2 17.5±0.9 N/D JG3 83.8 ± 2.6 N/D JG4 93.5 ± 0.4 N/D JG5 62.0 ± 8.9 N/D JG6 60.3 ± 3.6 N/D JG7 48.2 ± 6.7 N/D JG12 6.7 8.8 JG13 54 6.1 JG14 > 100 50 JGI5 46.2 54 JGI6 57 81.5 JGI7 60.2 >100 JG18 85.5 >100 JGI9 98 > 100 Copper chloride 48.4 ± 8.5 N/D Cobalt thiocyanate 76.2 ± 10.4 N/D lron(ll) perchlorate > 100 N/D Table 8. 1C50 values for different cancer cell lines treated for 96h with compounds of the present invention ic £IIM±ESEIM) ss s tratmit A428 HK-2 Hep-O ctiang cHo. cwc DU-145 P3 MCF-7 MDA-M 8-231 DJO2 48.4± >101) >100 >101) 95.9± >11)0 >100 >100 >100 >101) 2.5 1.2 JIJS 62.0± 44.2± 81.1'± 41.1 ± >100 >100 >100 >100 >100 512± ligand 8.9 34 4.9 09 2.7 J62 f75± 6±Th 209 ± 224± 204± 287± 172 ± 252± 7± ccirrç'Iex 0.9 42 H.1 19 2.2 24 2.6 1fl 0.7 02 Table 9. 1C50 values for A498 cancer cells treated for 96h with Compound JG2 of the present invention compared to cis-platin.
_____ Drug: _____ lCa cuM_±_S.E.M.) Jol 2a5±1.1 J03 sas±2.6 J04 9a5±U.4 610*0 J06 oaa±3.6 JOY 4EL2±6.Y JO@ 6E5±2.0 J09 1D0 JL.TI0 I IGlI ________________________ Copper chloride 44 ±85 I Li-itt tl*ii''' -IrlitH 1 -± lii 4 Iron (II) perchlortte:i 00 Material and Methods 1H and 13C NMR (5 ppm; J Hz) spectra were recorded on a JEOL JNM-LA300 FT-NMR spectrometer using saturated 00013 solutions with Me4Si reference, unless indicated otherwise, with resolutions of 0.18 Hz and 0.01 ppm, respectively. Multiplicities were given as follows: s (singlet), br (broad), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), m (multiplet). The number of protons (n) for a given resonance is indicated by n H. Coupling constants are reported as J values in Hertz. Infrared spectra (cm1) were recorded as KBr discs or liquid films between KBr plates using a Nicolet Impact 410 FT-IR. Melting point analysis was carried out using a Stewart Scientific SMP 1 melting point apparatus and are uncorrected. Mass spectra were carried out in the Mass Spectrometry unit in the Centre for Synthesis and Chemical Biology, University College, Dublin. Magnetic moments were measured Microanalyses were carried out at the Microanalytical Laboratory of University College, Dublin. Standard Schlenk techniques were used throughout. Starting materials were commercially obtained and used without further purification.
Synthesis of 2-(2H-tetrazol-5-yl)pyrid me (LI) A suspension of 2-cyanopyridine (4.14 g, 40 mmol), sodium azide (5.72 g, 90 mmol), ammonium chloride (4.70 g, 90 mmol) and lithium chloride (1.2 g, 280 mmol) in anhydrous dimethylformamide (40 ml) was stirred for 10 hours at 110 °C. After this time, the solution was cooled and the insoluble salts were removed by filtration. The solvent was then evaporated under reduced pressure and the residue was dissolved in deionised water (200m1) and acidified with concentrated HCI (3m1), to initiate precipitation. The product was removed by filtration, washed with water (3 x 40 ml) and dried to give a brown solid. This was recrystallised from hot ethanol to afford LI as brown needles (3 g, yield 51.3 %). m.p. 221-223 °C. C5H5N5 (147.14): calcd. C 48.98, H 3.43, N 47.60; found C 48.97, H 3.44, N 47.61. 1H NMR (CD3OD): 5 = 8.76 (d, 1 H, J = 7.9 Hz, pyr-H), 8.25 (d, 1 H, J = 7.9 Hz, pyr-H), 8.03 (t, I H, J = 7.9 Hz, pyr-H), 7.56 (t, I H, J = 7.9 Hz, pyr-H), 3.9 (s, 1 H, tet-H) ppm. 13C NMR (CD3OD): 5 154.9 (CN4), 150.1, 143.7, 138.3, 126.2, 122.7 ppm. MS(ES): m/z= 147.054[M = 147.054].
Synthesis of 2-(6"-bromohexyl-(I -tetrazol-5-yl)pyridine (L2) and 2-(6"-bromohexyl-(2-tetrazol- 5-yl)pyridine (L3) To LI (1 g, 6.8 mmol) dissolved in 2-butanone (30 ml) was added potassium carbonate (9.38 g, 68 mmol). The resulting solution was refluxed for 30 minutes and to the hot solution was added 1,6-dibromohexane (4.97 g, 24 mmol). The reaction mixture was then stirred at reflux temperature for a further 24 h. After cooling, the solvent was removed under reduced pressure to afford an oil, which was purified by column chromatography on silica gel (initially at a ratio of petroleum ether: ethyl acetate 80:20, followed by the ratio of 60:40). This gave the products L2 and L3.
JG4: Waxy white solid (0.55g, yield 26%). m.p. 39-41 °C. C12H16N5Br (310.19): calcd. C 46.46, H 5.20, N 22.58; found C 46.50, H 5.17, N 22.62. 1H NMR (CDCI3): 5 = 8.77 (d, 1 H, J = 7.5 Hz, pyr-H), 8.37 (d, I H, J = 7.5 Hz, pyr-H), 7.96 (t, I H, J 7.5 Hz, pyr-H), 7.52 (t, I H, J = 7.5 Hz, pyr-H), 5.00 (t, 2 H, J 6.9 Hz, CH2N), 3.42 (t, 2 H, J 6.9 Hz, CH2Br), 2.02 (q, 2 H, J= 7.1 Hz, CH2), 1.87(m, 2 H, CH2), 1.48(m, 4 H, CH2) ppm. 13C NMR (CDCI3): 5= 151.4 (CN4), 149.3, 144.6, 137.1, 125.1, 124.2, 49.2 (CH2N), 33.5 (CH2Br), 32.3, 32.1, 29.4, 27.2 ppm. MS (ES): m/z = 310.068 [M = 309.059].
JG5: Waxy white solid (0.35 g, yield 17 %). m.p. 36-38 °C. C12H15N5Br (310.19): calcd. C 46.46, H 5.20, N 22.58; found C 46.44, H 5.17, N 22.63. 1H NMR (CDCI3): 5 = 8.80 (d, 1 H, J = 7.7 Hz, pyr-H), 8.27 (d, I H, J = 7.7 Hz, pyr-H), 7.90 (t, I H, J 7.7 Hz, pyr-H), 7.43 (t, I H, J = 7.7 Hz, pyr-H), 4.73 (t, 2 H, J= 6.8 Hz, CH2N), 3.39 (t, 2 H, J= 6.8 Hz, CH2Br), 2.13 (q, 2 H, J= 6.8 Hz, CH2), 1.83(m, 2 H, CH2), 1.51 (m, 4 H, CH2) ppm. 13C NMR (CDCI3): 5= 164.7 (CN4), 150.2, 146.7, 137.1, 124.8, 122.3, 53.2 (CH2N), 33.4 (CH2Br), 32.4, 32.2, 29.0, 27.3 ppm. MS (ES): m/z = 3 10.066 [M = 309.0591.
General complexation reactions The appropriate 5-(2-pyridyl)-tetrazole ligand, L2 or L3 (0.20 g, 1.36 mmol), was dissolved in methanol (30 mL) and was added to a solution of the appropriate metal salt (1.36 mmol) in methanol (25 mL). The resulting highly-coloured solution was then heated to reflux for 2 h before being allowed to stand at room temperature for several days.
[Cu(JG4)C12]2 (JGI) Dark green crystals (0.137 g, yield 49%). C24H32Br2CLCu2N0 (889.29): calcd. C 32.41, H 3.63, N 15.75; found 032.52, H 3.71, N 15.73. IR (KBr): u = 2923, 2852, 1648, 1610, 1482, 1256, 1167, 1139, 1019, 803, 723 cmT Magnetic moment: 2.6 B.M.
(Cu(JG5)C12]2 (JG2) Dark green crystals (0.140 g, yield 50%). C24H32Br2CLCu2N10 (889.29): calcd. C 32.41, H 3.63, N 15.75; found 032.42, H 3.51, N 15.78. IR (KBr): u = 2923, 2856, 1648, 1610, 1483, 1278, 1165, 1019, 803, 721 cm1. Magnetic moment: 3.2 B.M.
Co(J04)2(NCS)2 (JG3) Rust coloured crystals (0.130 g, yield 26%). C26H32Br2CoN12S2 (795.48): calcd. C 39.26, H 4.05, N 21.13; found 039.31, H 4.09, N 21.18. IR (KBr): u = 2933, 2861, 2075, 1648, 1473, 1368, 1247, 1159, 1105, 1047, 795, 728 cml Magnetic moment: 4.5 B.M.
Co(JG5)2(NCS)2 (JG6) Green crystals (0.146 g, yield 29%). C23H32Br2CoN12S2 (795.48): calcd. 039.26, H 4.05, N 21.13; found 039.65, H 4.19, N 20.86. IR (KBr): u = 2928, 2858, 2075, 1654, 1474, 1368, 1247, 1159, 1105, 1047, 796, 728 cml Magnetic moment: 3.65 B.M.
Fe(JG4)2(C104)2(H20)2 (JG7) Yellow crystals (0.09 g, yield 16%). C24H36Br2C12FeN10O10 (911.16): calcd. 031.64, H 3.98, N 15.37; found 031.62, H 3.91, N 15.41. IR(KBr): u = 3407, 2924, 2852, 1637, 1478, 1379, 1250, 1143, 1112, 798, 727 cml Magnetic moment: 4.7 B.M.
Fe(JG5)2(Cl04)2(H20)2 (JG7) Yellow solid (0.11 g, yield 20%). C24H36Br2012FeN10O10 (911.16): calcd. 031.64, H 3.98, N 15.37; found 031.59, H 3.98, N 15.48. IR (KBr): u = 3410, 2942, 2862, 1638, 1451, 1384, 1145, 1117, 1089, 731 cml Magnetic moment: 5.0 B.M.
Crystallography All data sets were collected at 150(2) K on a Bruker APEXII COD diffractometer. In each case, Mo-Ka radiation (X = 0.7 1073 A) was used, a multi-scan correction was applied and the structures were refined against F2 using all the reflections.2° All non-hydrogen atoms were refined with anisotropic atomic displacement parameters and hydrogen atoms were placed at calculated positions and refined using a riding model.
Model cell lines A human renal adenocarcinoma cell line (A-498) initially harvested from a 52 year old female was used. They were purchased from the American Type Culture Collection (ATCC), Manassas, VA. The A-498 cell line (serial passage number: 81-10 1) has adherent growth properties with epithelial morphology and are tumorigenic in nude mice. They were maintained in Eagles Minimum Essential Medium (EMEM) with Earle's balanced salt solution (EBSS) containing 1.5 gIL sodium bicarbonate, 2 mM L-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100 UImL penicillin, pg/mL streptomycin and 10% (vlv) foetal bovine serum (FBS). Cells were grown until 70-80 % confluent in 25cm2 flasks (using 5 mL of medium) or 75 cm2 flasks (using 10 mL of medium). Cells were incubated at 37°C in a humidified atmosphere containing 95 % air, 5 % CO2.
Harvesting and subculture of cells A-498 cells possess adherent growth properties and required trypsinisation prior to subculture. For subculture, the spent medium was removed and the cells were washed with sterile PBS (0.1 M PBS, pH 7.4). Cells were detached from the culture flask by the addition of five mL trypsin solution [0.25 % (wlv) trypsin, 0.03 % (w/v) EDTA in 0.1 M PBS, pH 7.4]. The flask was then incubated at 37°C until the cells were fully detached. Trypsinisation was terminated by the addition of five mL of complete medium. Disaggregated cells were harvested by centrifugation at 1500 rpm for five minutes. The resultant pellet was resuspended in 3 mL of fresh media and seeded into new flasks at a subcultivation ratio of 1:6.
Cell counting and viability testing Cell counts were performed using a haemocytometer counting chamber (improved Neubauer model) under an Olympus CK-2 phase contrast microscope. Cellular viability was estimated by exclusion of the vital dye, trypan blue (0.4 % w/v). Viable cells exclude the dye while dead cells stain blue. 30 pL of cell suspension was added to 30 pL of trypan blue and incubated for five minutes. A l2pL aliquot of the solution was loaded into both counting chambers and cells were counted in the four corner squares along with the middle square. The average count from both chambers was then multiplied by five to adjust for the total number of chamber squares, then by the dilution factor and finally by i04 to account for the chamber volume. In this manner, a value representing the number of cells per volume was obtained.
Assessment of anti-proliferative activity using MTT assay Each test agent was dissolved in methanol or ethanol, diluted in culture media and used to treat A- 498 cells at various drug concentrations for a period of 96 hi, prior to MTT assay. The maximum percentage of solvent present in any well was 0.5% (vlv). Cells were seeded in sterile 96 well flat-bottomed plates (Sarstedt) at a density of 2.5x104 cells/mI and grown in 5% CO2 at 37 °C. At the end of the required incubation period, a miniaturised viability assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was carried out. In metabolically active cells, MTT is reduced by the mitochondrial enzyme succinate dehydrogenase to form insoluble purple formazan crystals that are subsequently solubilised, and the optical density (OD) measured spectrophotometrically.
Drug-treated cells were assayed by the addition of 20 p1 of 5 mg/mI MTT in 0.1 M phosphate buffer saline (PBS), pH 7.4. Following incubation for 4 h at 37 °c, the overlying medium was aspirated with a syringe and 100 p1 of DMSO was added to dissolve the formazan crystals. Plates were agitated at high speed to ensure complete dissolution of crystals and OD was measured at 550 nm using an Anthos HT-ll microtitreplate reader. Viability was expressed as a percentage of solvent-treated control cells. This assay had five replicates and each experiment was carried out on at least three separate occasions. The 1050 was calculated and defined as the drug concentration (pM) causing a 50% reduction in cellular viability.
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