CN103588782A - Gambogellic acid as well as preparation method and application thereof to medicines - Google Patents
Gambogellic acid as well as preparation method and application thereof to medicines Download PDFInfo
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- CN103588782A CN103588782A CN201310294148.6A CN201310294148A CN103588782A CN 103588782 A CN103588782 A CN 103588782A CN 201310294148 A CN201310294148 A CN 201310294148A CN 103588782 A CN103588782 A CN 103588782A
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Abstract
The invention relates to a caged polyprenylated xanthones compound, namely gambogellic acid, which has the anti-tumor activity. The invention also relates to a preparation method of the gambogellic acid. The preparation method comprises the following steps: with gambogic acid as a raw material, heating and carrying out preparative liquid chromatography separation, thus obtaining the gambogellic acid. The invention also relates to the application of the gambogellic acid to the preparation of anti-tumor medicines.
Description
Technical field
The present invention relates to a kind of many isopentene groups of cage shape xanthones compounds and preparation method thereof and in application pharmaceutically.
Background technology
Along with the impact of the factors such as living standard raising, increasing environmental pollution, the sickness rate of malignant tumour is soaring just year by year.Existing antitumor drug kind is limited, and toxic side effect is large, can not meet clinical medication demand far away.
Gamboge is that the trunk of guttiferae (Guttifera) plant gamboge tree (Garcinia hanburyiHook F.G.) is hurt the rear secreted colloidal resin going out.Be reddish yellow or orange red, main product Cambodia, Thailand and Vietnam, there is cultivation in China Guangdong Province and Hainan Province.Gamboge is resin 70%-80%, the miscellany of gummy 15%-25% etc.Wherein contain morellic acid (gambogic acid) 22.75%-36.59%, the compositions such as neogambogic acid (neogambogic acid), allogambogic acid (allogambogic acid).The traditional Chinese medical science is used for attacking poison, detumescence, the rotten sore of dispelling, hemostasis, desinsection.Cure mainly swollen ulcer drug, ulcer, wet sore, tumour, stubborn dermatitis, wound, wound hemorrhage and scald.External as diuretic(s), hypotensive etc. when treatment oedema and hematencephalon, record in American Pharmacopeia the tenth edition.Over nearly more than 20 years, particularly Chinese scholar has been done a large amount of research work to gamboge and activeconstituents morellic acid etc. thereof both at home and abroad.It is remarkable that gamboge and morellic acid etc. are used for the treatment of tumor efficiency, and toxic side effect is little, and activeconstituents stable in properties has caused extensive concern.
Raw product gamboge is very toxic, and severe patient is acutely suffered from diarrhoea, suffered from abdominal pain, and even dewater, suffer a shock, therefore generally can not take orally, be mainly external curing swollen ulcer drug, stubborn dermatitis.Life product gamboge, after the process of preparing Chinese medicine, not only guarantee the cleanliness of medicine, and after system, toxicity reduces, can supply to take orally, and for wound, metal-inflicted wound pyogenic infections, tumour, as multitude's cave ball.
Gamboge medication starts from the Tang Dynasty, its process of preparing Chinese medicine starts from the Qing Dynasty, traditional concocting method of gamboge mainly contains clear water system (being loaded in < < A Supplement to the Compendium of Materia Medica > >), lotus leaf system (being loaded in < < Yizong Jinjian > >), bean curd system and Sanguis Naemorhedi system (be loaded in < < surgery card and control complete raw collection > >).Modern times are mainly to tend to two kinds of methods to the process of preparing Chinese medicine of gamboge: clear water system and high pressure steaming, have auxiliary material and be easy to get, the feature such as easy to operate.
The structural formula of morellic acid (Gambogic acid) is as follows:
In prior art, gamboge olefin(e) acid (Gambogellic acid) is known compound, and its structural formula is as follows:
Research shows, morellic acid has had significant proliferation restraining effect to human hepatocellular carcinoma SMMC-7721 cell strain and QGY-7701 cell strain, and is dose-dependently, and to a little less than the effect relatively of normal people's hepatic tissue L-02 cell strain.The main toxicity of morellic acid is hepatic disorder, pain.
In sum, in view of medicine for treating tumor article kind in prior art is limited and toxic side effect is large, invent that new compound is very necessary safely and effectively.
Summary of the invention
One of technical problem to be solved by this invention is to provide a kind of compound with anti-tumor activity.
Another technical problem to be solved by this invention is to provide a kind of method of preparing above-claimed cpd.
The present invention wants the technical problem of technical solution to be also that above-claimed cpd can be used for preparing antitumor drug.
In order to solve the problems of the technologies described above, the present invention proposes following technical proposal:
The gamboge alkyd that following formula represents (Gambogollic acid), its structural formula is:
The preparation method of described gamboge alkyd, is characterized in that described method is comprised of the following step:
(1) get morellic acid, the water that adds its quality 80-120 doubly to measure, oil bath reflux 24-60h, concentrating under reduced pressure evaporate to dryness, obtains residue;
(2) prepare liquid phase separation:
Chromatographic condition is as follows: take specification as 10 μ m, the μ Bondapark C18 post of 19mm * 300mm is chromatographic column; Methyl alcohol-1% Glacial acetic acid that the volume ratio of take is 85: 15 is moving phase, and flow velocity is 16mL/min, and detection wavelength is 360nm, and column temperature is 30 ℃;
Get front step gained residue, by moving phase, dissolve, filter, inject preparative liquid chromatograph, collecting appearance time is the cut between 10-12min, merges, and is evaporated to dryly, obtains.
The application of described gamboge alkyd in preparing antitumor drug.
The preparation of gamboge alkyd and the data of structure elucidation are shown in test one.
Preparation and the structure elucidation of test one, gamboge alkyd.
1 preparation method: press embodiment 3 preparations.
2 Structural Identification data are as follows:
The spectral data of 2.1 reference compound gamboge olefin(e) acid Gambogellic acid
Gamboge olefin(e) acid (Gambogellic acid) is dissolved in to deuterochloroform, take TMS as interior mark, detect, its NMR data are in Table 1:
The nuclear-magnetism related data of table 1 gamboge olefin(e) acid
The Structural Identification of 2.2 gamboge alkyd
2.2.1UV identify
Get appropriate compound, take methyl alcohol as solvent, make the solution that concentration is 0.01mg/mL, under room temperature, (25 ℃) detect, and the absorption spectrum of ultraviolet is shown in Figure of description 1, and obtained the maximum absorption is at 215nm, 362nm, compares with morellic acid, has lacked the uv-absorbing at 280nm place.
2.2.2MS identify
Get appropriate compound, take methyl alcohol as solvent, make the solution that concentration is 0.01mg/mL, take methyl alcohol-1% acetic acid as moving phase, wriggling sample introduction 5 μ L.The results are shown in Figure of description 2, high resolution mass spectrum provides compound [M+H]
+quasi-molecular ion peak m/z647.3352, the molecular formula of determining this compound is C
38h
46o
9, m/z629 is its [M-H
2o]
+peak, m/z573 is its [M-H
2o-C
4h
7]
+peak, m/z679 is its [M+Na]
+peak.
2.2.3NMR identify
Compound is dissolved in to deuterochloroform, take TMS as interior mark, detect, the results are shown in Figure of description 3-8.The NMR data of compound are in Table 2:
The nuclear-magnetism related data of table 2 gamboge alkyd
2.2.4 the structure elucidation of compound
Yellow oily compound, is soluble in chloroform, yellow intensification after 10% ethanol solution of sulfuric acid colour developing, and prompting may be xanthone compounds.
1in H-NMR spectrum, provide hydroxyl proton signal δ 13.77 (1H, s) that associate with carbonyl, the alkene hydrogen proton signal on two typical isopentene groups, δ 5.05 and δ 6.12 (each, 1H, m), in addition, visible 8 unimodal proton signals of methyl, lay respectively at δ 0.84, δ 1.20, δ 1.30, δ 1.38, δ 1.64, δ 1.72, δ 1.72 and δ 1.73 (each, 3H, s).
13in C-NMR spectrum, provide altogether 38 carbon signals, wherein, δ c203.4 is ketone carbonyl signal, and δ c179.0 is beta-unsaturated ketone carbonyl signal, and δ c170.2 is carboxyl signal.
1in H-NMR spectrum, δ 3.48 (1H, dd, J=4.5,6.9Hz, H-11), δ 2.31 (1H, dd, J=4.5,9.2Hz, Ha-21) and δ 2.56 (1H, d, J=9.2Hz, Ha-22) are the feature proton signal on dicyclo [2,2,2] octane.Three oxygen carbon signal δ c90.7 of company, δ c84.1, δ c84.0 in conjunction with occurring in carbon spectrum, can infer that this compound is many isopentene groups of cage shape xanthones compounds.Compare with the spectral data of known compound gamboge olefin(e) acid Gambogellic acid, many unimodal proton signals of methyl, have lacked terminal double link proton signal, are judged as ethylene linkage and the water generation addition reaction of C-38, C-40 position.Meanwhile, in the ROESY of compound spectrum, can see the locus coherent signal of H-37 and H-19, prompting 19-methyl, 4-H and 37-H are at the homonymy of six-ring.Through retrieval, compound is one to have no the new compound of bibliographical information, called after gamboge alkyd Gambogollic acid.Its structural formula is shown in Figure of description 9.
The antineoplastic pharmacologically active of gamboge alkyd can embody by following test.
The restraining effect research of test example two gamboge alkyd to liver cancer cell SMMC-7721, Human normal hepatocyte L-02
1 experiment material
1.1 medicine
Gamboge alkyd, by embodiment 3 preparations.Morellic acid, self-control.
1.2 main agents, consumptive material
New-born calf serum (FBS): Hangzhou Sijiqing Biological Engineering Material Co., Ltd.;
RPMI Medium1640 substratum: GIBCO
tMinvitrogen Corporation, Cat.No.31800-014.Lot No.1279327;
Costar96 orifice plate, Tissue Culture Flask, U.S. Corning company;
Dimethyl sulfoxide (DMSO) (DMSO), Biosharp company, Lot:2010/10;
Tetrazolium bromide (MTT): Biosharp, Lot:2010/08;
NaCl: Shantou Xilong Chemical Factory Co., Ltd, analytical pure, lot number: 080916;
KCl: Nanjing chemical reagent factory, analytical pure, lot number: 830602;
KH
2pO
4: Shanghai reagent two factories, analytical pure; Lot number: 950215;
Na
2hPO
4-12H
2o: Shanghai Ling Feng chemical reagent company limited, analytical pure; Lot number: 080102;
Water is ultrapure water, and other reagent is analytical pure.
1.3 key instrument
Microplate reader: Power Wave X340, BIO-TEK INTRUMENTS, Inc
Bechtop: Suzhou City treating plant company limited;
LDZ5-2 low speed autobalancing centrifuge: Beijing Medical Centrifugal Machine Factory;
Serious?II?water?jacketed?CO
2?Incubator：Thermo?Electron?Corporation；
Olympus CKX31 microscope
The upper Nereid of electronic balance: FA2004N section (ten thousand/), Sartorius BT125D (100,000/)
Portable pressure steam sterilizing device YXQ.SG41.280, Shanghai Huaxian Medical Nuclear Instruments Co., Ltd.
1.4 cell strain
Human liver cancer cell SMMC-7721, research emphasis laboratory is concocted in people's normal cell lines of human liver L-02 ，You Jiangsu Province and clinical pharmacology laboratory provides.
2 methods and result
The preparation of 2.1 main agents
2.1.1PBS the preparation of solution
Precision takes NaCl4g, KCl0.1g, Na
2hPO
41.74g, KH
2pO
40.1g, adds ultrapure water 500mL, and continuously stirring 15min is to dissolving completely.
2.1.2RPMI1640 substratum
Get RPMI Medium1640 culture medium powder, separately add NaHCO
31.70g, adding ultrapure water 1000mL, continuously stirring 30min is to dissolving completely.
2.1.3 the preparation of pancreatin solution
Precision takes trypsinase 0.25g, adds PBS solution 100mL, mixes.
Above-mentioned solution, in super clean bench, with aseptic injection filter (the aseptic millipore filtration of 0.22 μ m) filtration sterilization, is distributed into bottle, and 4 ℃ save backup.
2.1.4MTT the preparation of liquid
Take MTT powder, add appropriate PBS solution, vortex dissolves, and makes into the solution that concentration is 5mg/mL.
The configuration of 2.2 test liquids
2.2.1 the preparation of sample solution
Precision takes compound gamboge alkyd 1.02mg, and morellic acid 1.14mg, adds respectively appropriate DMSO, ultrasonic to dissolving completely.
Before administration, with RPMI1640 substratum, be diluted to 0.25 μ mol/L, 0.5 μ mol/L, 1 μ mol/L, 2 μ mol/L, 4 μ mol/L, 8 μ mol/L, a series of concentration such as 16 μ mol/L, 4 ℃ save backup.
2.2.2 Western medicine positive drug solution
Get DDP (trade(brand)name: mother liquor cis-platinum) (1mg/mL), is diluted to 2 μ g/mL with RPMI1640 substratum before administration.
2.2.3 the preparation of blank group solution
Draw the DMSO of certain volume, with RPMI1640 substratum, be diluted to the concentration of needs, be the highlyest no more than 5 ‰.
3 Related Components are to Normocellular toxicity test
The cultivation of 3.1 normal cell lines of human liver L-O2
Normal cell lines of human liver L-O2 cellar culture is in containing the RPMI1640 substratum of 15% calf serum.Be placed in 37 ℃, 5%CO
2cultivate in incubator, when being cultured to 70%-80% and merging, 0.25% tryptic digestion, go down to posterity, maintain suitable cell concn.
3.2MTT method is measured cell proliferation inhibition rate
The normal cell lines of human liver L-O2 that the ox of taking the logarithm is long-term, PBS cleans 2-3 time, adds 0.25% pancreatin solution digestion, treat cell retraction, become circle, pancreatin in time inclines, in cell bottle, add the RPMI1640 substratum containing 15% calf serum, the cell on piping and druming bottle wall, is dispersed in substratum cell.Draw a small amount of cell suspension, under microscope, count, regulating cell concn is 5 * 10
4/ mL.Be inoculated in 96 porocyte culture plates every hole 100 μ L.After cell attachment, after (about 24h), inhale and abandon medium supernatant in hole gently, add the hungry 24h of RPMI1640 substratum.Inhale and abandon medium supernatant in hole gently, add respectively the sample solution 200 μ L:0.25 μ mol/L with different concns, 0.5 μ mol/L, 1 μ mol/L, 2 μ mol/L, 4 μ mol/L, 8 μ mol/L, 16 μ mo]/L ... each concentration is established 6 multiple holes, and establishes blank group and the Western medicine positive drug control group that does not contain sample.Cultivate after 44h, every hole adds after the MTT solution 20 μ L effect 4h of 5mg/mL, inhales and abandons culture supernatant in hole gently, and every hole adds DMSO solution 150 μ L light shaking 10min, and crystallisate is fully dissolved, withered with blank well.At enzyme-linked immunosorbent assay instrument 490nm wavelength place, measure each hole optical density value (OD value), ask its mean value.With blank group cellular control unit survival rate, be designated as 100%.
3.3 experimental result
By following formula, calculate: experimental group cell inhibitory rate %=(1-experimental group OD value/control group OD value) * 100%, with drug level (μ mol/L) and inhibiting rate (%), do linear regression, calculate the half-inhibition concentration IC of this medicine to normal cell lines of human liver L-O2
50.
The IC of table 3 compound to normal cell lines of human liver L-O2
50calculation result
The antitumour drug effect card of 4 Related Components
The cultivation of 4.1 liver cancer cell SMMC-7721
Liver cancer cell SMMC-7721 cellar culture is in containing the RPMI1640 substratum of 10% calf serum.Be placed in 37 ℃, 5%CO
2cultivate in incubator, when being cultured to 70%-80% and merging, 0.25% tryptic digestion, go down to posterity, maintain suitable cell concn.
4.2MTT method is measured cell proliferation inhibition rate
The liver cancer cell SMMC-7721 taking the logarithm vegetative period, PBS cleans 2-3 time, adds 0.25% pancreatin solution digestion, treat cell retraction, become circle, pancreatin in time inclines, in cell bottle, add the RPMI1640 substratum containing 10% calf serum, the cell on piping and druming bottle wall, is dispersed in substratum cell.Draw a small amount of cell suspension, under microscope, count, regulating cell concn is 5 * 10
4/ mL.Be inoculated in 96 porocyte culture plates every hole 100 μ L.After cell attachment, after (about 24h), inhale and abandon medium supernatant in hole gently, add the hungry 24h of RPMI1640 substratum.Inhale and abandon medium supernatant in hole gently, add respectively the sample solution 200 μ L:0.25 μ mol/L with different concns, 0.5 μ mol/L, 1 μ mol/L, 2 μ mol/L, 4 μ mol/L, 8 μ mol/L ... each concentration is established 6 multiple holes, and establishes blank group and the Western medicine positive drug control group that does not contain sample.Cultivate after 44h, every hole adds after the MTT solution 20 μ L effect 4h of 5mg/mL, inhales and abandons culture supernatant in hole gently, and every hole adds DMSO solution 150 μ L light shaking 10min, and crystallisate is fully dissolved, withered with blank well.At enzyme-linked immunosorbent assay instrument 490nm wavelength place, measure each hole optical density value (OD value), ask its mean value.With blank group cell survival rate, be designated as 100%.
4.3 experimental result
By following formula, calculate: experimental group cell inhibitory rate %=(1-experimental group OD value/control group OD value) * 100%, with drug level (μ mol/L) and inhibiting rate (%), do linear regression, calculate the half-inhibition concentration IC of this medicine to liver cancer cell SMMC-7721
50.
The IC of table 4 compound to tumour cell SMMC-7721
50calculation result
5 conclusions
If single from IC
50analyze, compound gamboge alkyd will be better than morellic acid to the inhibition of liver cancer cell SMMC-7721, and its toxicity to normal cell lines of human liver L-O2 is lower than morellic acid.
Gamboge alkyd is during for the preparation of application in antitumor drug, and its oral or parenteral administration is all safely and effectively.Oral administration can be made any regular dosage form, as: powder, particle, capsule, sheet, orally disintegrating tablet, dripping pill, soft capsule etc.; Parenteral administration, can be made into various regular dosage forms, as injection liquid etc.
Gamboge alkyd is during for the preparation of antitumor drug, and its auxiliary material and preparation method can select the acceptable form of any pharmacy.
The dosage of gamboge alkyd can change according to the factors such as age, coincident with severity degree of condition of taking mode, patient, and adult's oral dosage is 1-200mg/ day, and adult injection dosage is 1-50mg/ day.
Accompanying drawing explanation
Below in conjunction with embodiment, the present invention is further illustrated:
The ultra-violet absorption spectrum of Fig. 1 gamboge alkyd;
The mass spectrum of Fig. 2 gamboge alkyd;
Fig. 3 gamboge alkyd
1h-NMR spectrogram
Fig. 4 gamboge alkyd
13c-NMR collection of illustrative plates
The H-H COSY collection of illustrative plates of Fig. 5 gamboge alkyd
The HSQC collection of illustrative plates of Fig. 6 gamboge alkyd
The HMBC collection of illustrative plates of Fig. 7 gamboge alkyd
The ROESY collection of illustrative plates of Fig. 8 gamboge alkyd
The structural formula of Fig. 9 gamboge alkyd
Embodiment
Following embodiment can better illustrate the present invention, and it does not limit protection domain of the presently claimed invention in any form.
The preparation of embodiment 1 gamboge alkyd
(1) get morellic acid, add the water of 80 times of amounts of its quality, oil bath reflux 24h, concentrating under reduced pressure evaporate to dryness, obtains residue;
(2) prepare liquid phase separation:
Chromatographic condition is as follows: take specification as 10 μ m, the μ Bondapark C18 post of 19mm * 300mm is chromatographic column; Methyl alcohol-1% Glacial acetic acid that the volume ratio of take is 85: 15 is moving phase, and flow velocity is 16mL/min, and detection wavelength is 360nm, and column temperature is 30 ℃;
Get front step gained residue, by moving phase, dissolve, filter, inject preparative liquid chromatograph, collecting appearance time is the cut between 10-12min, merge, be evaporated to dryly, obtain yellow oily compound 14.3mg, through HPLC normalization method, detect, purity is 96.2%, and its spectral data is consistent with the content of recording above.
The preparation of embodiment 2 gamboge alkyd
(1) get morellic acid, add the water of 120 times of amounts of its quality, oil bath reflux 60h, concentrating under reduced pressure evaporate to dryness, obtains residue;
(2) prepare liquid phase separation:
Chromatographic condition is as follows: take specification as 10 μ m, the μ Bondapark C18 post of 19mm * 300mm is chromatographic column; Methyl alcohol-1% Glacial acetic acid that the volume ratio of take is 85: 15 is moving phase, and flow velocity is 16mL/min, and detection wavelength is 360nm, and column temperature is 30 ℃;
Get front step gained residue, by moving phase, dissolve, filter, inject preparative liquid chromatograph, collecting appearance time is the cut between 10-12min, merge, be evaporated to dryly, obtain yellow oily compound 16.8mg, through HPLC normalization method, detect, purity is 96.1%, and its spectral data is consistent with the content of recording above.
The preparation of embodiment 3 gamboge alkyd
(1) get morellic acid, add the water of 100 times of amounts of its quality, oil bath reflux 48h, concentrating under reduced pressure evaporate to dryness, obtains residue;
(2) prepare liquid phase separation:
Chromatographic condition is as follows: take specification as 10 μ m, the μ Bondapark C18 post of 19mm * 300mm is chromatographic column; Methyl alcohol-1% Glacial acetic acid that the volume ratio of take is 85: 15 is moving phase, and flow velocity is 16mL/min, and detection wavelength is 360nm, and column temperature is 30 ℃;
Get front step gained residue, by moving phase, dissolve, filter, inject preparative liquid chromatograph, collecting appearance time is the cut between 10-12min, merges, and is evaporated to dry, obtain yellow oily compound 16.1mg, through HPLC normalization method, detect, purity is 96.6%.
The preparation of embodiment 4 gamboge alkyd sheets
Tablet: gamboge alkyd 20mg, starch 180g, granulates, and compressing tablet is made 1000.Instructions of taking: be grown up one time 1,3 times on the one.
Claims (3)
1. the gamboge alkyd that following formula represents, its structural formula is:
2. the preparation method of gamboge alkyd described in claim 1, is characterized in that described method is comprised of the following step:
(1) get morellic acid, the water that adds its quality 80-120 doubly to measure, oil bath reflux 24-60h, concentrating under reduced pressure evaporate to dryness, obtains residue;
(2) prepare liquid phase separation:
Chromatographic condition is as follows: take specification as 10 μ m, the μ Bondapark C18 post of 19mm * 300mm is chromatographic column; Methyl alcohol-1% Glacial acetic acid that the volume ratio of take is 85: 15 is moving phase, and flow velocity is 16mL/min, and detection wavelength is 360nm, and column temperature is 30 ℃;
Get front step gained residue, by moving phase, dissolve, filter, inject preparative liquid chromatograph, collecting appearance time is the cut between 10-12min, merges, and is evaporated to dryly, obtains.
3. the application of gamboge alkyd claimed in claim 1 in preparing antitumor drug.
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| US10868366B2 (en) | 2017-01-04 | 2020-12-15 | Intel Corporation | Package architecture for antenna arrays |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000044216A2 (en) * | 1999-02-01 | 2000-08-03 | Cytovia Inc | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
| CN1563014A (en) * | 2004-04-16 | 2005-01-12 | 杭州民生药业集团有限公司 | New compound ramification of garcinia acid |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000044216A2 (en) * | 1999-02-01 | 2000-08-03 | Cytovia Inc | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
| CN1563014A (en) * | 2004-04-16 | 2005-01-12 | 杭州民生药业集团有限公司 | New compound ramification of garcinia acid |
Non-Patent Citations (2)
| Title |
|---|
| 冯锋，等: "藤黄酸及其类似物抗肿瘤的定量构效关系", 《中国医科大学学报》, vol. 38, no. 4, 31 August 2007 (2007-08-31), pages 311 - 314 * |
| 林昌军，等: "藤黄科植物中具有桥环结构的天然产物全合成研究进展", 《有机化学》, vol. 28, no. 2, 31 December 2008 (2008-12-31), pages 218 - 277 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10868366B2 (en) | 2017-01-04 | 2020-12-15 | Intel Corporation | Package architecture for antenna arrays |
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