WO1997010263B1 - Actinomycin d analogues - Google Patents
Actinomycin d analoguesInfo
- Publication number
- WO1997010263B1 WO1997010263B1 PCT/DK1996/000386 DK9600386W WO9710263B1 WO 1997010263 B1 WO1997010263 B1 WO 1997010263B1 DK 9600386 W DK9600386 W DK 9600386W WO 9710263 B1 WO9710263 B1 WO 9710263B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- alkyl
- hydrogen
- immobilised
- array
- Prior art date
Links
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical class C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract 39
- 125000004122 cyclic group Chemical group 0.000 claims abstract 25
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract 19
- 238000002360 preparation method Methods 0.000 claims abstract 4
- 125000003118 aryl group Chemical group 0.000 claims abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 52
- -1 -O-R6 Chemical group 0.000 claims 35
- 229910052739 hydrogen Inorganic materials 0.000 claims 31
- 239000001257 hydrogen Substances 0.000 claims 31
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims 30
- 125000001424 substituent group Chemical group 0.000 claims 26
- 125000003107 substituted aryl group Chemical group 0.000 claims 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 16
- 125000004429 atoms Chemical group 0.000 claims 12
- 239000000463 material Substances 0.000 claims 12
- 239000007787 solid Substances 0.000 claims 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 11
- 230000000875 corresponding Effects 0.000 claims 11
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 8
- 230000015572 biosynthetic process Effects 0.000 claims 6
- 238000006664 bond formation reaction Methods 0.000 claims 6
- 230000001808 coupling Effects 0.000 claims 6
- 238000010168 coupling process Methods 0.000 claims 6
- 238000005859 coupling reaction Methods 0.000 claims 6
- 238000005755 formation reaction Methods 0.000 claims 6
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000004104 aryloxy group Chemical group 0.000 claims 5
- 125000001246 bromo group Chemical group Br* 0.000 claims 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims 5
- 125000004185 ester group Chemical group 0.000 claims 5
- 125000001153 fluoro group Chemical group F* 0.000 claims 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 5
- 229910052736 halogen Inorganic materials 0.000 claims 5
- 150000002367 halogens Chemical class 0.000 claims 5
- 125000002346 iodo group Chemical group I* 0.000 claims 5
- 239000000126 substance Substances 0.000 claims 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims 4
- 229910006069 SO3H Inorganic materials 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- RGEVWUKXWFOAID-UHFFFAOYSA-N Piperidione Chemical compound CCC1(CC)C(=O)CCNC1=O RGEVWUKXWFOAID-UHFFFAOYSA-N 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
- 150000008064 anhydrides Chemical group 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 229960003810 piperidione Drugs 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- MNFORVFSTILPAW-UHFFFAOYSA-N Β-Lactam Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- MGNZXYYWBUKAII-UHFFFAOYSA-N 1,3-Cyclohexadiene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims 1
- ZHKJHQBOAJQXQR-UHFFFAOYSA-N 1H-azirine Chemical compound N1C=C1 ZHKJHQBOAJQXQR-UHFFFAOYSA-N 0.000 claims 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N Azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N Cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N Cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims 1
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N Dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 claims 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N Oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N Thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 claims 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N Tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 claims 1
- MDYOLVRUBBJPFM-UHFFFAOYSA-N Tropolone Chemical compound OC1=CC=CC=CC1=O MDYOLVRUBBJPFM-UHFFFAOYSA-N 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 230000000844 anti-bacterial Effects 0.000 claims 1
- 230000001093 anti-cancer Effects 0.000 claims 1
- 230000001532 anti-fungicidal Effects 0.000 claims 1
- 230000000840 anti-viral Effects 0.000 claims 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims 1
- 230000003115 biocidal Effects 0.000 claims 1
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 230000002363 herbicidal Effects 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 1
- 229940113083 morpholine Drugs 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 1
- 150000004713 phosphodiesters Chemical group 0.000 claims 1
- 125000003386 piperidinyl group Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 150000003235 pyrrolidines Chemical class 0.000 claims 1
- 150000003568 thioethers Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract 2
- 229920000160 (ribonucleotides)n+m Polymers 0.000 abstract 1
- 108010069514 Cyclic Peptides Proteins 0.000 abstract 1
- 102000001189 Cyclic Peptides Human genes 0.000 abstract 1
- 108010092160 Dactinomycin Proteins 0.000 abstract 1
- 229960000640 Dactinomycin Drugs 0.000 abstract 1
- 150000001371 alpha-amino acids Chemical class 0.000 abstract 1
- 235000008206 alpha-amino acids Nutrition 0.000 abstract 1
- 150000001576 beta-amino acids Chemical class 0.000 abstract 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 abstract 1
- 239000000138 intercalating agent Substances 0.000 abstract 1
- 238000010647 peptide synthesis reaction Methods 0.000 abstract 1
- 239000007790 solid phase Substances 0.000 abstract 1
Abstract
The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by α-amino acids, β-amino acids and/or longer chain φ-amino acids, and a difunctional group which preferably is a cyclic entity, in particular, an aromatic or heteroaromatic entity acting as an intercalator group. Specific compounds and a library of such compounds may be prepared using conventional solid phase peptide synthesis (SPPS) methodologies. The novel compounds are expected to have affinity for DNA and RNA, and libraries thereof may therefore advantageously be used for screening purposes. Furthermore, a novel double-combinatorial technique that may be used in the preparation of librairies of broader classes of compounds has been developed.
Claims
1. A compound of the following general formula I: 
wherein A designates a cyclic or linear entity; and each of P1 and P2 independently designates a linear or cyclic moiety comprising 4-20 units of the general formula II
wherein n is 0 or 1;
each of R1, R2, R3, R4 independently is a side chain selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted C1-6-alkenyl, optionally substituted C2-8-alkadienyl, optionally substituted C6-8-alkatrienyl, hydroxy, -O-R6, formyl, -C(=O)-R6, -O-C(=O)-R6, carboxy, -C(=O)-O-R6, optionally substituted heteroaryl, (optionally substituted heteroaryl)-C1-6-alkyl, (optionally substituted heteroaryloxy)-C1-6-alkyl, optionally substituted aryl, (optionally substituted aryl)-C1- 6-alkyl, (optionally substituted aryloxy)-C1-6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, nitro, cyano, amino, -NHR6, -N(R6)2, mono- or di(C1-6-alkyl)amino-C1-6-alkyl, -N(R7)-CO-R6, (C1-20-alkyl)carbonylamino-C1-6-alkyl, carbamoyl, aminocarbonyl-C1-6-alkyl, mono- or di(C1-20-alkyl)aminocarbonyl, mono- or di(C1 -6-alkyl)aminocarbonyl-C1-6-alkyl, sulphanyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, (optionally substituted aryl)thio, guanidino, guanidino-C1-6-alkyl, sulphono (-SO3H), sulphino (-SO2H), halosulphonyl, -OS(O)m-R6 where m is 2 or 3, -N(R7)S(O)m-R6 where m is 2 or 3, -S(O)m-N(R7)2 where m is 2 or 3, -S(O)m-NH(R7) where m is 2 or 3, -S(O)m-NH2 where m is 2 or 3, isocyano isothiocyano, thiocyano. OP(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is I or 2, and p+q is 3, 4, or 5;
wherein each R6 independently is selected from hydrogen, optionally substituted C1-20- alkyl, optionally substituted C1-20-alkenyl, optionally substituted C1-20-alkadienyl, optionally substituted C1-20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each R7 is selected from hydrogen and C1-4-alkyl; and R6 is selected from hydrogen and C1-4-alkyl; and wherein one of the substituent pairs R1/R2, R1/R3, and R3/R4 may form a biradical which, together with the atoms located between these substituents (Cα and/or Cβ), forms a ring: or one of the substituent pairs R2/R6 and R4/R5 may form a biradical which, together with the atoms located between these substituents (Cα, Cβ, and/or N), forms a ring; and, if any of P1 and P2 is a cyclic moiety, the cyclic character arises from the presence of a linkage between two of the side chains, R1, R2, R3, and R4, of two units of the formula II within a moiety P1 and/or P2.
2. A compound according to claim 1, wherein at least one of P1 and P2 is a cyclic moiety
3. A compound according to claim 2, wherein both of P1 and Ps are cyclic moieties.
4. A compound according to any of the claims 2-3, wherein the linkage comprises a group selected from an amide group (-NR5-C(=O)-), a disulphide group (-S-S-), an ester group (-C(=O)- O-), an ether group (-O-), phosphodiester group (-O-P(O)2-O-), and a sulphide group (-S-).
5. A compound according to any of the preceding claims, wherein the moieties P1 and P2 each comprises 4-15, preferably 4-10, in particular 5-8, units of the formula II.
6 A compound according to any of the preceding claims, wherein the number of units in the moiety P1 is identical to the number of units in the moiety P2.
7. A compound according to any of the preceding claims, wherein the moieties P1 and P2 are substantially identical.
8. A compound according to any of the preceding claims, wherein each of the side chains R1, R2. R3, and R4 independently is selected from hydrogen, optionally substituted C1-6-alkyl, hydroxy, -O-R6, carboxy, -C(=O)-O-R5, optionally substituted aryl, optionally substituted heteroaryl, sulphanyl, carbamoyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, guanidino, guanidino-C1-6-alkyl, -OP(O)p(R5)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4 or 6, and -N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4 or 5;
wherein each R6 independently is selected from hydrogen, optionally substituted C1-20-alkyl, and optionally substituted aryl; and each R7 is selected from hydrogen and C1-4-alkyl
9. A compound according to any of the preceding claims, where one of the substituent pairs R1/R2, R1/R5, and R3/R4, together with the atoms located between these substituents (Cα and/or Cβ), forms a ring of one of the types cyclopropane, oxirane, aziridine, cyclopropane, azirine, cyclobutane, oxetane, azetidine, thietane, 2-azetidinone, 1,3-lactone, pyrolidine, pyroline, pyrrole, cyclopcaetene, cyclopentadiene, pyrollidione, pyrollidone, cyclohexyl, oxirane, dioxirane morpholine, piperidine, 1,5-lactone, 1,5-lactam, cyclohexene, cyclohexadiene, piperidione, tropane, 1,6-lactone (tropolone), or 1,6 -lactam which may be optionally substituted;
or one of the substituent pairs R2/R6 and R4/R5, together with the atoms located between these substituents (Cα, Cβ, and/or N), forms a ring of one of the types 2-azetidinone, pyrolidine.
pyroline, pyrrole, pyrollidione, pyrollidone. piperidine, 1,5-lactam, piperidione, and 1,6-lactam.
10. A compound according to any of the claims 1-8, wherein none of the substituent pairs R'/R2. R1/R3, R3/R4, and R4/R5 are involved in ring(s).
11. A compound according to any of the preceding claims, wherein the units of the moieties P1 and P1 have the formula IIa
wherein each of the side chains R1 and R2 independently is selected from hydrogen, optionally substituted C1-6-alkyl, hydroxy, -O-R6, carboxy, -C(=O)-O-R6, optionally substituted aryl, optionally substituted heteroaryl, sulphanyl. carbanoyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, guanidino guanidino-C1-6-alkyl,-OP(O)p(R6)q where p is 1, 2. or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5; wherein each R6 independently is selected from hydrogen, optionally substituted C1-20-alkyl, and optionally substituted aryl; and each R7 and R8 independently are selected from hydrogen and C1-4-alkyl.
12. A compound according to any of the preceding claims, wherein one of the side chains R1 and R2 is hydrogen and the other side chain is selected from hydrogen, optionally substituted C1-6-alkyl, hydroxy, -O-R6, carboxy, -C(=O)-O-R6, optionally substituted aryl, optionally substituted heteroaryl, sulphanyl, carbanoyl, optionally substituted C1-20-alkylthiυ, optionally substituted C1-20-alkylthio-C1-6-alkyl, guanidino, guanidino-C1-6-alkyl, -OP(O)p(R6)q where p is 1 , 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and•N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5; wherein each R6 independently is selected from hydrogen, optionally substituted C1-10-alkyl. and optionally substituted aryl; and each R7 is selected from hydrogen and C1-4-alkyl R5 is hydrogen; or the substituent pair R2/R6 together with the intervening carbon (Cα) and nitrogen atoms form an optionally substituted pyrrolidine or piperidine ring.
13. A compound according to any of the preceding claims, wherein the entity A is a cyclic entity.
14. A compound according to claim 13, wherein the cyclic entity A is an optionally substituted aromatic or polyaromatic entity.
15. A compound according to any of the claims 1-12, wherein the entity A is a linear or carbocyclic entity.
16. A compound according to any of the preceding claims, wherein at least one of the moieties P1 and P2 includes 1-18, preferably 1-2, units of the formula III 
wherein the methylene groups are optionally substituted one or several times, preferably 1-3 times, with group(s) as defined in claim 1 for R 1-R4, and wherein where R5' designates the same groups as defined in claim 1 for R5.
17. A method for the preparation of a compound of the following formula I 
wherein A designates a cyclic or linear entity; and each of P1 and P2 independently designates a linear or cyclic moiety comprising 1-20 units, preferably 2-20 units, of the general formula II
wherein n is 0 or 1;
each of R1, R2, R3 R4 independently is a side chain selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted C1-0-alkenyl, optionally substituted C2-5-alkadienyl, optionally substituted C6-8-alkatrienyl, hydroxy, -O-R6, formyl, -C(=O)-R5, -O-C(=O)-R5, carboxy, -C(=O)-
O-R6, optionally substituted heteroaryl, (optionally substituted heteroaryl)-C1-6-alkyl, (optionally substituted heteroaryloxy)-C1-6-alkyl, optionally substituted aryl, (optionally substituted aryl)-C1- 6-alkyl, (optionally substituted aryloxy)-C1-6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, nitro, cyano, amino, -NHR6, -N(R5)a, mono- or di(C1-6-alkyl)amino-C1-6-alkyl, -N(R7)-CO-R6, (C1-20-alkyl)carbonylamino-C1-6-alkyl, carbamoyl, aminocarbonyl-C1-6-alkyl, mono- or di(C1-20- alkyl)aminocarbonyl, mono- or di(C1-6-alkyl)aminocarbonyl-C1-6-alkyl, sulphanyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, (optionally substituted aryl)thio, guanidino, guanidino-C1-6-alkyl, sulphono (-SO3H), sulphino (-SO2H), halosulphonyl, -OS(O)m-R6 where m is 2 or 3, -N(R7)S(O)m-R6 where m is 2 or 3, -S(O)m-N(R7)2 where m is 2 or 3, -S(O)m-NH(R7) where m is 2 or 3, -S(O)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5;
wherein each R6 independently is selected from hydrogen, optionally substituted C1-20- alkyl, optionally substituted C1-20-alkenyl, optionally substituted C1-20-alkadienyl, optionally substituted C1-20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each R7 is selected from hydrogen and C1-4-alkyl; and
R5 is selected from hydrogen and C1-4-alkyl; and wherein one of the substituent pairs R1/R2, R1/R3, and R3/R4 may form a biradical which, together with the atoms located between these substituents (Cα and/or Cβ), forms a ring; or one of the substituent pairs R2/R5 and R4/R5 may form a biradical which, together with the atoms located between these substituents (Cα, Cβ, and/or N), forms a ring; and if any of P1 and P2 is a cyclic moiety, the cyclic character arises from the presence of a linkage between two of the side chains, R1, R2, R3, and R4, of two units of the formula II within a moiety P1 and/or P2, comprising the following steps (A) providing an optionally side chain protected moiety P1 immobilised to a solid support material, the α- or β-amino group of the N-terminal unit (the unit neighbouring the carbonyl group (C(=O)) located between P1 and A) of the immobilised moiety P1 being unprotected; (B) coupling a diacid HOOC-A-COOH, in the free acid, monoester, or internal anhydride form, to the unprotected amino group of the N-terminal unit of the immobilised moiety P1 for the formation of an immobilised fragment P1-C(=O)-A-COOH in the tree acid or ester form, (C) cleaving the fragment P1-C(=O)-A-COOH, optionally in the eater form, from the solid support material: (D) providing an optionally side chain protected moiety P2 immobilised to a solid support material, the α- or β-amino group of the N-terminal unit of the immobilised moiety P2 (the unit neighbouring the carbonyl group (C(=O)) located between P2 and A) being
unprotected; (E) coupling the fragment P1-C(=O)-A-COOH to the immobilised moiety P2 for the formation of an immobilised compound P1-C(=O)-A-C(=O)-P2; and
(F) cleaving the compound P1-C(=O)-A-C(=O)-P2 from the solid support material.
18. A method for the preparation of a multi-dimensional array of compounds, {P1}-{A}-{P2}, consisting of at least four compounds each having the general formula I
P1 - C ( =O) -A- C ( =O) - P2 I wherein A designates a cyclic or linear entity; and each of P1 and P2 independently designates a linear or cyclic moiety comprising 1 -20 units, preferably 2-20 units, of the general formula II
wherein n is 0 or 1 ;
each of R1, R2, R3, R4 independently is a side chain selected from hydrogen, optionally substituted
C1-6-alkyl, optionally substituted C1-6-alkenyl, optionally substituted C2-8-alkadienyl, optionally substituted C6-8-alkatnenyl, hydroxy, -O-R6, formyl, -C(=O)-R6, -O-C(=O)-R6, carboxy, -C(=O)-
O-R6, optionally substituted heteroaryl, (optionally substituted heteroaryl)-C1-6-alkyl, (optionally substituted heteroaryloxy)-C1-6-alkyl, optionally substituted aryl, (optionally substituted aryl)-C1- 6-alkyl, (optionally substituted aryloxy)-C1-6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, nitro, cyano. amino, -NHR6, -N(R5)2, mono- or di(C1-6-alkyl)amino-C1-6-alkyl, -N(R7)-CO-R6, (C1- 20-alkyl)carbonylamino-C1-6-alkyl, carbamoyl, aminocarbonyl-C1-6-alkyl, mono- or di(C1-20-alkyl)aminocarbonyl, mono- or di(C1-6-alkyl)aminocarbonyl-C1-6-alkyl, sulphanyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, (optionally substituted aryl)thio, guanidino, guanidino-C1-6-alkyl, sulphono (-SO3H), sulphino (-SO2H), halosulphonyl, -OS(O)m-R6 where m is 2 or 3, -N(R7)S(O)m-R6 where m is 2 or 3, -S(O)m-N(R7)2 where m is 2 or 3, -S(O)m-NH(R7) where m is 2 or 3, -S(O)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5;
wherein each R6 independently is selected from hydrogen, optionally substituted C1-20- alkyl, optionally substituted C1-20-alkenyl, optionally substituted C1-20-alkadienyl, optionally substituted C1-20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each R7 is selected from hydrogen and C1-1-alkyl; and
R5 is selected from hydrogen and C1-4-alkyl; and wherein one of the substituent pairs R1/R2, R1/R3, and R3/R4 may form a biradical which, together with the atoms located between these substituents (Cα and/or Cβ), forms a ring; or one of the substituent pairs R2/R5 and R4/R5 may form a biradical which, together with the atoms located between these substituents (Cα, Cβ, and/or N), forms a ring; and, if any of P1 and P2 is a cyclic moiety, the cyclic character arises from the presence of a linkage between two of the aide chains, R1, R2, R3, and R4, of two units of the formula II within a moiety P1 and/or P2, comprising the following steps:
(A) providing an array {P1} of at least two optionally side chain protected moieties P1 immobilised to a solid support material, the α- or β-amino group of the N-terminal unit of the immobilised moieties P1 being unprotected; (B) coupling an array {A} of one or more diacids, HOOC-A-COOH, in the free acid, monoester or internal anhydride form, to the unprotected amino groups of the N-terminal unit of the immobilised moieties P1 for the formation of an array {P1}-{A} of immobilised fragments P1-C(=O)-A-COOH, optionally in the ester form; (C) cleaving the array {P1}-{A} of fragments P1-C(=O)-A-COOH, optionally in the ester form, from the solid support material; (D) providing an array {P2} of at least two optionally side chain protected moieties P2 immobilised to a solid support material, the α- or β-amino group of the N-terminal unit of the immobilised moieties P2 being unprotected, (E) coupling the array {P1}-{A} of fragments P1-C(=O)-A-COOH, optionally in the ester form, to the array {P2} of immobilised moieties P2 for the formation of an array {P1}-{A}-{P2} of immobilised compounds P1-C(=O)-A-C(=O)-P2; and
(F) cleaving the array {P1}-{A}-{P2} of immobilised compounds P1-C(=O)-A-C(=O)-P2 from the solid support material.
19. A method according to claim 18, wherein the array {P2} of immobilised moieties P2 is substantially identical to the array {P1} of immobilised moieties P1.
20. A method according to claim 19, wherein the array {P1} of immobilised moieties P1 and the array {P2} of immobilised moieties P2 are prepared in one batch.
21. A method for the preparation of a multi-dimensional array {L1}-{B}-{L2} of at least four compounds each having the formula L1-B-L2, wherein the arrays {L1} and {L2} are of similar chemical composition, each of L1 and L2 includes a fragment l1 and l2, respectively, of a chemical functionality, B is an entity which includes two fragments b1 and b2 of chemical functionalities, each of the fragment seta l1b1 and b2l2 forming a covalent linkage between L1 and B and between B and L2, respectively, said covalent linkages/links being substantially identical and being formed under b/l bond formation reaction conditions, the method comprising the following operations:
(A) providing an array {L} of at least two moieties L immobilised to a solid support material, where the array {L} has similar chemical composition to the arrays {L1} and {L2}, each of the moieties L includes a group comprising a fragment 1 of a chemical functionality, where the fragment l is identical to the fragments l1 and l2, the groups corresponding to the fragment 1 being in protected or unprotected form and any other groups of L sensitive to b/l bond form anon reaction conditions being optionally protected;
(B) dividing the solid support material representing the array {L} into two parts to give arrays {L1} and {L2), respectively, the array {L1} comprising immobilised moieties designated L1 and the array {L2} comprising immobilised moieties designated L2;
(C) in the case where the group corresponding to the fragment l1 is protected deprotecting said group, (D) under b/l bond formation reaction conditions, coupling an array {B} of one or more compounds corresponding to the entity/entities B to the array {L1} for the formation of an array {L1}-{B} of immobilised compound fragments L1-B, where the b/l bond formation reaction involves the group corresponding to b1 of the compounds corresponding to the entity/entities B and the group corresponding to l1 of the immobilised moieties L1, the group corresponding to b2 of the entity/entities B and any other groups sensitive to b/l bond formation reaction conditions optionally being protected; (E) cleaving the array {L1}-{B} of immobilised compound fragments L1-B from the solid support material;
(F) if necessary, deprotecting the group corresponding to the fragment b2;
(G) in the case where the group corresponding to the fragment l2 is protected, deprotecting said group;
(H) under b/1 bond formation reaction conditions, coupling the array {L1}-(B} of compound fragments L1-B to the array {L2} for the formation of a multi-dimensional array {L1}-{B}- {L2} of immobilised compounds L1-B-L2, the b/l bond formation reaction involving the group corresponding to l2 and the group corresponding to b2; and
(J) cleaving the multi-dimensional array {L1}-{B}-{L2} of immobilised compounds L1-B-L2 from the solid support material.
22. The use of a multi-dimensional array of compounds of the general formula I
P1 - C (=O) -A- C (=O) - P2 I wherein A designates a cyclic or linear entity; and each of P1 and P2 independently designates a linear or cyclic moiety comprising 1-20 units, preferably 2-20 units, of the general formula II
each of R1, R2, R3, R4 independently is a side chain selected from hydrogen, optionally substitutedC1-6-alkyl, optionally substituted C1-6-alkenyl, optionally substituted C2-8-alkadienyl, optionally substituted C6- 8-alkatrienyl, hydroxy, -O-R6, formyl, -C(=O)-R6, -O-C(=O)-R6, carboxy -C(=O)- O-R6, optionally substituted heteroaryl, (optionally substituted heteroaryl)-C1-6-alkyl (optionally substituted heteroaιyloxy)-C1-6-alkyl, optionally substituted aryl, (optionally substituted aryl)-C1- 8-alkyl, (optionally substituted aryloxy)-C1-6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, nicro, cyano, amino, -NHR6 -N(R6)2, mono- or di(C1-6-alkyl)amino-C1-6-alkyl -N(R7)-CO-R6, ( C1 -20-alkyl)carbonylamino-C1-6-alkyl, carbamoyl, aminocarbonyl-C1 s-alkyl, mono- or di( C1 -20-alkyl)aminocarbonyl, mono- or di(C1-6-alkyl)aminocarbonyl-C1-6-alkyl, sulphanyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, (optionally substituted aryl)thio, guanidino, guarudino-C1-6-alkyl, sulphono (-SO2H), sulphino (-SO2H), halosulphonyl -OS(O)m-R6 where m is 2 or 3, -N(R7)S(O)m-R6 where m is 2 or 3, -S(O)m-N(R7)2 where m is 2 or 3 -S(O)m-NH(R7) where m is 2 or 3, -S(O)m-NH2 where m is 2 or 3, isocyano, isothiocyano, thiocyano, -OP(O)P(R6)q where p is 1, 2 or 3, q is 1 or 2, and p+q is 3 4, or 5, and•N(R7)P(O)p(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5,
wherein each R6 independently is selected from hydrogen, optionally substituted C1 -20- alkyl, optionally substituted C1 -20-alkenyl, optionally substituted C1 -20- alkadienyl, optionally substituted C1 -20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl, and
each R7 is selected from hydrogen and C1-4- alkyl, and
R5 is selected from hydrogen and C1-4-alkyl, and wherein one of the substituent pairs R1/R2, R1/R3, and R3/R4 may form a biradical which together with the atoms located between these substituents (Cα and/or Cβ) forms a ring; or one of the substituent paire R2/R5 and R4/R5 may form a biradical which, together with the atoms located between these substituents (Cα, Cβ, and/or N), forms a ring, and, if any of P1 and P2 is a cyclic moiety, the cyclic character arises from the presence of a linkage between two of the side chains, R1, R2, R3, and R4, of two units of the formula II within a moiety P1 and/or P2 for screening purposes.
23. The use of a compound of the general formula (1)
P1 - C ( =O ) -A- C ( =O) - P2 I wherein A designates a cyclic or linear entity; and each of P1 and P2 independently designates a linear or cyclic moiety comprising 1-20 units, preferably 2-20 units, of the general formula II
wherein n is 0 or 1;
each of R1, R2, R3, R4 independently is a side chain selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted C1-6-alkenyl, optionally substituted C2-8-alkadienyl, optionally substituted C6-8-alkatrienyl, hydroxy, -O-R6, formyl, -C(=O)-R6, -O-C(=O)-R6, carboxy, -C(=O)-O-R6, optionally substituted heteroaryl, (optionally substituted heteroaryl)-C1-6-alkyl, (optionally-substituted heteroaryloxy)-C1-6-alkyl, optionally substituted aryl, (optionally substituted aryl)-C1- 6-alkyl, (optionally substituted aryloxy)-C1-6-alkyl, halogen such as fluoro, chloro, bromo, and iodo, nitro, cyano, amino, -NHR6, -N(R6)2, mono- or di(C1-6-alkyl)amino-C1-6-alkyl, -N(R7)-CO-R6, ( C1 -20-alkyl)carbonylamino-C1-6-alkyl, carbamoyl, aminocarbonyl-C1-6-alkyl, mono- or di(C1-20-alkyl)aminocarbonyl, mono- or dl(C1-6-alkyl)aminocarbonyl-C1-6-alkyl, sulphanyl, optionally substituted C1-20-alkylthio, optionally substituted C1-20-alkylthio-C1-6-alkyl, (optionally substituted aryl) thio, guanidino, guaiudino-C1-6-alkyl, sulphono (-SO2H), sulphino (-SO2H), halosulphonyl, -OS(O)m-R6 where m is 2 or 3, -N(R7)S(O)m-R6 where m is 2 or 3, -S(O)m-N(R7)2 where m is 2 or 3, -S(O)m-NH(R7) where m is 2 or 3, -S(O)m-NH2 where m is 2 or 3, isocyano isothiocyano, thiocyano, -OP(O)p(R6)α where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5, and -N(R7)P(O)P(R6)q where p is 1, 2, or 3, q is 1 or 2, and p+q is 3, 4, or 5,
wherein each R6 independently is selected from hydrogen, optionally substituted C1-20- alkyl, optionally substituted C1 -20-alkenyl, optionally substituted C1-20-alkadienyl, optionally substituted C1-20-alkatrienyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each R7 is selected from hydrogen and C1-4-alkyl; and R6 is selected from hydrogen and C1-4-alkyl; and wherein one of the substituent pairs R1/R2, R1/R3, and R3/R4 may form a biradical which, together with the atoms located between these substituents (Cα and/or Cβ), forms a ring; or one of the substituent pairs R2/R5 and R4/R5 may form a biradical which, together with the atoms located between these substituents (Cα, Cβ, and/or N), forms a ring; and, if any of P1 and P2 is a cyclic moiety, the cyclic character arises from the presence of a linkage between two of the side chains, R1, R2, R3, and R4, of two units of the formula II within a moiety P1 and/or P2 for antiviral, anticancer, antibiotic such as antibacterial and antifungicidal, or herbicidal purposes.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9511577A JP2000501068A (en) | 1995-09-12 | 1996-09-12 | Actinomycin D analog |
| AU68698/96A AU6869896A (en) | 1995-09-12 | 1996-09-12 | Actinomycin d analogues |
| EP96929190A EP0862578A1 (en) | 1995-09-12 | 1996-09-12 | Actinomycin d analogues |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1009/95 | 1995-09-12 | ||
| DK100995 | 1995-09-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1997010263A1 WO1997010263A1 (en) | 1997-03-20 |
| WO1997010263B1 true WO1997010263B1 (en) | 1997-05-01 |
Family
ID=8099977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DK1996/000386 WO1997010263A1 (en) | 1995-09-12 | 1996-09-12 | Actinomycin d analogues |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0862578A1 (en) |
| JP (1) | JP2000501068A (en) |
| AU (1) | AU6869896A (en) |
| WO (1) | WO1997010263A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19942624A1 (en) * | 1999-08-28 | 2001-03-08 | Chemotopix Gmbh | Process for the preparation of cyclic peptidomimetics |
| BR112017022605A2 (en) * | 2015-04-23 | 2018-07-17 | Viiv Healthcare Uk No 5 Ltd | "compound, composition, and method for treating hiv infection". |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3954970A (en) * | 1974-05-24 | 1976-05-04 | Schering Corporation | Actinomycin complex from micromonospora |
| US4562176A (en) * | 1985-10-03 | 1985-12-31 | Sengupta Sisir K | Method and composition for treating cancer |
| US4680382A (en) * | 1986-02-03 | 1987-07-14 | Trustees Of Boston University | Analogues of actinomycin D |
| EP0823486A3 (en) * | 1991-06-27 | 2004-02-11 | Genelabs Technologies, Inc. | Method for inhibiting the binding of a dna-binding protein to duplex dna |
| EP0672084B2 (en) * | 1992-11-30 | 2007-03-07 | Bulk Chemicals, Inc. | A method and composition for treating metal surfaces |
-
1996
- 1996-09-12 JP JP9511577A patent/JP2000501068A/en active Pending
- 1996-09-12 AU AU68698/96A patent/AU6869896A/en not_active Abandoned
- 1996-09-12 EP EP96929190A patent/EP0862578A1/en not_active Withdrawn
- 1996-09-12 WO PCT/DK1996/000386 patent/WO1997010263A1/en not_active Application Discontinuation
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