NGHIÊN CỨU TỔNG HỢP VÀ HOẠT TÍNH SINH HỌC CÁC DẪN XUẤT MỚI CỦA ALKALOID DỪA CẠN LUẬN ÁN TIẾN SỸ HÓA HỌC

BỘ GIÁO DỤC VÀ ĐÀO TẠO VIỆN HÀN LÂM KHOA HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ - VÕ NGỌC BÌNH NGHIÊN CỨU TỔNG HỢP VÀ HOẠT TÍNH SINH HỌC CÁC DẪN XUẤT MỚI CỦA ALKALOID DỪA CẠN Chuyên ngành: Hóa Hữu Mã số: 44 01 14 LUẬN ÁN TIẾN SỸ HÓA HỌC NGƯỜI HƯỚNG DẪN KHOA HỌC: PGS.TS Ngơ Quốc Anh TS Đồn Duy Tiên Hà Nội – 2018 Lời cam đoan Tôi xin cam đoan cơng trình nghiên cứu riêng tơi cộng Các số liệu kết nêu Luận án trung thực chưa cơng bố cơng trình nghiên cứu trước Tồn thơng tin trích dẫn Luận án rõ nguồn gốc xuất xứ Hà Nội, Ngày tháng Tác giả Võ Ngọc Bình I năm 2018 Lời cảm ơn Với lòng biết ơn sâu sắc, xin gửi lời cảm ơn tới tập thể thầy cô hướng dẫn khoa học PGS.TS Ngơ Quốc Anh TS Đồn Duy Tiên - Viện Hóa học, Viện Hàn lâm Khoa học Cơng nghệ Việt Nam giao đề tài trực tiếp định hướng, bảo giúp đỡ tơi tồn q trình thực Luận án Tơi xin chân thành cảm ơn Thầy, Cô, cán Viện Hóa học, Viện Hàn lâm Khoa học Cơng nghệ Việt Nam giảng dạy, hướng dẫn tơi hồn thành học phần chuyên đề Chương trình đào tạo Tơi xin gửi lời cảm ơn chân thành đến ThS Nguyên Lê Anh, ThS Nguyễn Thị Hằng, ThS Trần Thị Yến, CN Phạm Tùng Lâm cán bộ, nhân viên Trung tâm nghiên cứu xuất sắc liên ngành lĩnh vực hợp chất thiên nhiên Việt Nam – Vương Quốc Anh, Viện Hóa học tạo điều kiện giúp đỡ suốt thời gian thực Luận án Cuối cùng, xin gửi lời cảm ơn đến gia đình, bạn bè đồng nghiệp động viên, giúp đỡ mặt suốt trình thực Luận án Trân trọng cảm ơn ! Tác giả Võ Ngọc Bình II “All sciences are vain and full of errors that are not born of Experience, the mother of all Knowledge”  Leonardo da Vinci III MỤC LỤC Danh mục ký hiệu, chữ viết tắt vii Danh mục bảng x Danh mục hình vẽ, sơ đồ .xi MỞ ĐẦU CHƯƠNG TỔNG QUAN 1.1 Microtubule - Một đích tác dụng quan trọng thuốc điều trị ung thư 1.1.1 Định nghĩa 1.1.2 Động học microtubule 1.1.3 Các nhóm thuốc chống ung thư theo chế tác dụng lên microtubule 1.2 Vinca alkaloid 1.2.1 Giới thiệu vinca alkaloid 1.2.2 Tổng hợp vinca alkaloid 10 1.2.2.1 Bán tổng hợp 11 1.2.2.2 Tổng hợp toàn phần 16 1.2.2.3 Sinh tổng hợp công nghệ sinh học 18 1.2.3 Mối quan hệ cấu trúc – hoạt tính vinca alkaloid 18 1.2.3.1 Những thay đổi phần khung vindoline 19 1.2.3.2 Những thay đổi phần khung velbanamine 21 1.2.4 Ứng dụng lâm sàng vinca alkaloid 27 1.3 Định hướng mục tiêu luận án 27 CHƯƠNG THỰC NGHIỆM 30 2.1 Hóa chất thiết bị 30 2.1.1 Hóa chất dung mơi 30 2.1.2 Thiết bị nghiên cứu 30 2.1.2.1 Phổ hồng ngoại IR 30 2.1.2.2 Phổ cộng hưởng từ hạt nhân NMR 30 2.1.2.3 Phổ khối lượng MS HRMS 30 2.1.2.3 Năng suất quay cực riêng [α]D 31 IV 2.2 Các phương pháp nghiên cứu 31 2.2.1 Các phương pháp tổng hợp hữu 31 2.2.2 Phương pháp thử hoạt tính sinh học 31 2.2.3 Các phương pháp tinh chế xác định cấu trúc 31 2.3 Tổng hợp số dẫn xuất vinca alkaloid chứa mạch nhánh ketone α,βkhông no 32 2.3.1 Tổng hợp anhydrovinblastine 12 32 2.3.2 Tổng hợp 18(S)-3’,5'-dimethoxyanilinecleavamine 77 33 2.3.3 Tổng hợp số dẫn xuất vinca alkaloid chứa mạch nhánh ketone α,β-không no 34 2.4 Tổng hợp số dẫn xuất vinca alkaloid từ 3’-cyanoanhydrovinblastine 88…… 46 2.4.1 Tổng hợp 3’-cyanoanhydrovinblastine 88 46 2.4.2 Tổng hợp dẫn xuất alkaloid thơng qua việc khử có chọn lọc dẫn xuất 3’-cyanoanhydrovinblastine 88 48 2.4.2.2 Tổng hợp chất 3'R-cyano-(4’S,5’-dihydro)-anhydrovinblastine 92a 48 2.4.2.2 Tổng hợp chất 3'R-cyano-(4’R,5’-dihydro)-anhydrovinblastine 92b 49 2.4.2.3 Tổng hợp chất (3'R-aminomethyl)-(4’S,5’-dihydro)-anhydrovinblastine 92c 51 2.4.2.4 Tổng hợp chất 3'S-cyano-4-deacetyl-anhydrovinblastine 92d 3'Scyano-4-deacetyl-3-hydroxymethyl-anhydrovinblastine 92e 52 2.4.3 Tổng hợp số dẫn xuất alkaloid thơng qua việc khử alkyl hóa aminomethyl 92c 54 2.5 Thử nghiệm hoạt tính sinh học chất nghiên cứu 61 2.5.1 Thử nghiệm hoạt tính gây độc tế bào in vitro 61 2.5.1.2 Thử nghiệm hoạt tính gây độc tế bào in vitro dịng tế bào ung thư biểu mơ KB ung thư gan HepG2 61 2.5.1.2 Thử nghiệm hoạt tính sinh học dòng tế bào ung thư bạch huyết cấp tính người HL-60 62 2.5.2 Phương pháp mơ hình mơ Docking phân tử 65 CHƯƠNG KẾT QUẢ VÀ THẢO LUẬN 68 3.1 Tổng hợp dẫn xuất vinca alkaloid chứa mạch nhánh ketone α,β-không no 68 V 3.2 Tổng hợp dẫn xuất vinca alkaloid từ 3’-cyanoanhydrovinblastine 88… 84 3.2.1 Tổng hợp dẫn xuất vinca alkaloid thông qua việc khử chọn lọc 3’-cyanoanhydrovinblastine 88 84 3.2.2 Tổng hợp dẫn xuất vinca alkaloid thơng qua việc khử alkyl hóa aminomethyl 92c 99 3.3 Đánh giá hoạt tính sinh học chất nghiên cứu 102 3.3.1 Đánh giá hoạt tính gây độc tế bào in vitro 102 3.3.1.1 Đánh giá hoạt tính gây độc tế bào ung thư biểu mô KB ung thư gan HepG2… 102 3.3.1.2 Đánh giá hoạt tính sinh học dịng tế bào ung thư bạch huyết cấp tính người HL-60 106 3.3.2 Kết Docking 115 3.3.2.1 Kết docking phân tử sử dụng phần mềm Autodock 4.0 116 3.3.2.2 Kết docking phân tử sử dụng phần mềm Patchdock 117 KẾT LUẬN 120 NHỮNG ĐIỂM MỚI CỦA LUẬN ÁN 121 DANH MỤC CƠNG TRÌNH CỦA TÁC GIẢ 122 TÀI LIỆU THAM KHẢO 123 PHỤ LỤC 139 VI DANH MỤC CÁC KÝ HIỆU, CÁC CHỮ VIẾT TẮT A ADME Absorption, Distribution, Metabolism, Excretion AVLB Anhydrovinblastine AZT Azidothymidine C 4CBL 4-chlorochablastine 4CCR 4-Chlorochacristine CC Column Chromatography COSY Correlation Spectroscopy CBPI Cytochalasin B proliferation index m-CPBA meta-Chloroperoxybenzoic acid 13 Carbon-13 Nuclear Magnetic Resonance spectroscopy C-NMR D DCM Dichloromethane DEPT Distortioless Enhancement by Polarisation Tranfer DMSO Dimethyl sulfoxide DABCO 1,4-Diazabicyclo(2.2.2)octane DMSO Dimethyl sulfoxide DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DMA 3,5-dimethoxyaniline DPAS Dihydroprecondylocarpine synthase E ESI-MS Electrospray Ionization Mass Spectroscopy EI-MS Electron Ionization Mass Spectroscopy EtOAc Ethyl acetate EtOH Ethanol VII F FDA Fluorescein diacetate H HRMS Hight resolution Mass Spectroscopy Proton Nuclear Magnetic Resonance Spectroscopy HSQC Heteronuclear Single Quantum Correlation HMBC Heteronuclear Multiple bond Correlation H-NMR s: singlet d: double t: triplet m: multiplet dd: double doublet Hep-G2 Human Heptocellular carcinoma HL-60 Human leukemia 60 h Hour q: quartet br: broad I IR Infrared Spectroscopy IC50 Inhibitory concentration of 50% of cell proliferation K KB Human epidemoid carcinoma M MeOH Methanol N NMR Nuclear Magnetic Resonance Spectroscopy NOESY Nuclear Overhauser Enhancement Spectroscopy NIS N-Iodosuccinimide P PAS Precondylocarpine acetate synthase PDB Protein data bank PBS Phosphate buffered saline R RT Room temperature VIII qui: quintet T TMS Tetramethyl silan THF Tetrahydrofuran TFA Trifluoroacetic acid TLC Thin Layer Chromatography V VBL Vinblastine VCR Vincristine VFL Vinflunine VRB Vinorelbine IX 31 Buey, R M.; Barasoain, I.; Jackson, E.; Meyer, A.; Giannakakou, P.; Paterson, I.; Mooberry, S.; Andreu, J M.; Díaz, J F., Microtubule interactions with chemically diverse stabilizing agents: thermodynamics of binding to the paclitaxel site predicts cytotoxicity Chemistry & Biology 2005, 12 (12), 1269-1279 32 Hamel, E.; Day, B W.; Miller, J H.; Jung, M K.; Northcote, P T.; Ghosh, A K.; Curran, D P.; Cushman, M.; Nicolaou, K.; Paterson, I., Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly Molecular Pharmacology 2006, 70 (5), 1555-1564 33 Huzil, J T.; Chik, J K.; Slysz, G W.; Freedman, H.; Tuszynski, J.; Taylor, R E.; Sackett, D L.; Schriemer, D C., A unique mode of microtubule stabilization induced by peloruside A Journal of Molecular Biology 2008, 378 (5), 1016-1030 34 Jordan, M A.; Kamath, K., How microtubule-targeted drugs work? An overview Current Cancer Drug Targets 2007, (8), 730-742 35 Zhou, J.; Giannakakou, P., Targeting microtubules for cancer chemotherapy Current Medicinal Chemistry-Anti-Cancer Agents 2005, (1), 65-71 36 Na, G C.; Timasheff, S N., Thermodynamic linkage between tubulin self- association and the binding of vinblastine Biochemistry 1980, 19 (7), 1355-1365 37 Na, G C.; Timasheff, S N., Stoichiometry of the vinblastine-induced self- association of calf brain tubulin Biochemistry 1980, 19 (7), 1347-1354 38 Lobert, S C., J , Academic Press: 2000; 323, 77–103 39 Duflos, A.; Kruczynski, A.; Barret, J.-M., Novel aspects of natural and modified vinca alkaloids Current Medicinal Chemistry-Anti-Cancer Agents 2002, (1), 55-70 40 Plosker, G L.; Figgitt, D P., Rituximab Drugs 2003, 63 (8), 803-843 41 Sandler, A B Chemotherapy for small cell lung cancer, Seminars in Oncology, 30(1) 2003; 9-25 42 Armitage, J O., Overview of rational and individualized therapeutic strategies for non-Hodgkin's lymphomas Clinical Lymphoma 2002, 3, S5-S11 43 Jassem, J.; Kosmidis, P.; Ramlau, R.; Zarogoulidis, K.; Novakova, L.; Breton, J.; Etienne, P.-L.; Seebacher, C.; Grivaux, M.; Ojala, A., Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer Annals of Oncology 2003, 14 (11), 1634-1639 125 44 Rossi, A.; Gridelli, C.; Gebbia, V.; Rosati, G.; Tortoriello, A.; Maione, P.; Borsellino, N.; Rossi, N.; Pisano, A.; Colantuoni, G., Single agent vinorelbine as firstline chemotherapy in elderly patients with advanced breast cancer Anticancer Research 2003, 23 (2C), 1657-1664 45 Seidman, A D Monotherapy options in the management of metastatic breast cancer, Seminars in Oncology, 2003, 30(2), 6-10 46 Okouneva, T.; Hill, B T.; Wilson, L.; Jordan, M A., The Effects of vinflunine, vinorelbine, and vinblastine on centromere dynamics1 Molecular Cancer Therapeutics 2003, (5), 427-436 47 Hastie, S B., Interactions of colchicine with tubulin Pharmacology & Therapeutics 1991, 51 (3), 377-401 48 Skoufias, D A.; Wilson, L., Mechanism of inhibition of microtubule polymerization by colchicine: inhibitory potencies of unliganded colchicine and tubulincolchicine complexes Biochemistry 1992, 31 (3), 738-746 49 Tozer, G M.; Kanthou, C.; Parkins, C S.; Hill, S A., The biology of the combretastatins as tumour vascular targeting agents International Journal of Experimental Pathology 2002, 83 (1), 21-38 50 Hamel, E.; Lin, C M.; Plowman, J.; Wang, H.-K.; Lee, K.-H.; Paull, K D., Antitumor 2, 3-dihydro-2-(aryl)-4 (1H)-quinazolinone derivatives: Interactions with tubulin Biochemical Pharmacology 1996, 51 (1), 53-59 51 Mabjeesh, N J.; Escuin, D.; LaVallee, T M.; Pribluda, V S.; Swartz, G M.; Johnson, M S.; Willard, M T.; Zhong, H.; Simons, J W.; Giannakakou, P., 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF Cancer Cell 2003, (4), 363-375 52 Lakhani, N J.; Sarkar, M A.; Venitz, J.; Figg, W D., 2‐Methoxyestradiol, a promising anticancer agent Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2003, 23 (2), 165-172 53 Yoshimatsu, K.; Yamaguchi, A.; Yoshino, H.; Koyanagi, N.; Kitoh, K., Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin Cancer Research 1997, 57 (15), 3208-3213 126 54 Horwitz, S B., How to make taxol from scratch Nature 1994, 367 (6464), 593- 594 55 Manfredi, J J.; Parness, J.; Horwitz, S B., Taxol binds to cellular microtubules The Journal of Cell Biology 1982, 94 (3), 688-696 56 Parness, J.; Horwitz, S B., Taxol binds to polymerized tubulin in vitro The Journal of Cell Biology 1981, 91 (2), 479-487 57 Diaz, J F.; Andreu, J M., Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition Biochemistry 1993, 32 (11), 2747-2755 58 Belani, C P.; Langer, C., First-line chemotherapy for NSCLC: an overview of relevant trials Lung Cancer 2002, 38, 13-19 59 Fossella, F V.; Lynch, T.; Shepherd, F A., Second line chemotherapy for NSCLC: establishing a gold standard Lung Cancer 2002, 38, 5-12 60 Bollag, D M.; McQueney, P A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C M., Epothilones, a new class of microtubulestabilizing agents with a taxol-like mechanism of action Cancer Research 1995, 55 (11), 2325-2333 61 Wartmann, M.; Altmann, K., The biology and medicinal chemistry of epothilones Current Medicinal Chemistry-Anti-Cancer Agents 2002, (1), 123-148 62 Lee, F Y.; Borzilleri, R.; Fairchild, C R.; Kim, S.-H.; Long, B H.; Reventos- Suarez, C.; Vite, G D.; Rose, W C.; Kramer, R A., BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy Clinical Cancer Research 2001, (5), 1429-1437 63 Kamath, K.; Jordan, M A., Suppression of microtubule dynamics by epothilone B is associated with mitotic arrest Cancer Research 2003, 63 (18), 6026-6031 64 ter Haar, E.; Kowalski, R J.; Hamel, E.; Lin, C M.; Longley, R E.; Gunasekera, S P.; Rosenkranz, H S.; Day, B W., Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol Biochemistry 1996, 35 (1), 243-250 65 Honore, S.; Kamath, K.; Braguer, D.; Wilson, L.; Briand, C.; Jordan, M A., Suppression of microtubule dynamics by discodermolide by a novel mechanism is associated with mitotic arrest and inhibition of tumor cell proliferation Molecular Cancer Therapeutics 2003, (12), 1303-1311 127 66 Hung, D T.; Chen, J.; Schreiber, S L., (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding and results in mitotic arrest Chemistry & Biology 1996, (4), 287-293 67 Kavallaris, M.; Verrills, N M.; Hill, B T., Anticancer therapy with novel tubulin- interacting drugs Drug Resistance Updates 2001, (6), 392-401 68 Kowalski, R J.; Giannakakou, P.; Gunasekera, S P.; Longley, R E.; Day, B W.; Hamel, E., The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells Molecular pharmacology 1997, 52 (4), 613-622 69 Panda, D.; Miller, H P.; Islam, K.; Wilson, L., Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action Proceedings of the National Academy of Sciences 1997, 94 (20), 10560-10564 70 Smaletz, O.; Galsky, M.; Scher, H.; DeLaCruz, A.; Slovin, S.; Morris, M.; Solit, D.; Davar, U.; Schwartz, L.; Kelly, W., Pilot study of epothilone B analog (BMS247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration Annals of Oncology 2003, 14 (10), 1518-1524 71 Kelly, W K.; Zhu, A X.; Scher, H.; Curley, T.; Fallon, M.; Slovin, S.; Schwartz, L.; Larson, S.; Tong, W.; Hartley-Asp, B., Dose escalation study of intravenous estramustine phosphate in combination with paclitaxel and carboplatin in patients with advanced prostate cancer Clinical Cancer Research 2003, (6), 2098-2107 72 Hudes, G.; Haas, N.; Yeslow, G.; Gillon, T.; Gunnarsson, P O.; Ellman, M.; Nordle, O.; Eriksson, B.; Miller, L.; Cisar, L., Phase I clinical and pharmacologic trial of intravenous estramustine phosphate Journal of Clinical Oncology 2002, 20 (4), 1115-1127 73 Dahllöf, B.; Billström, A.; Cabral, F.; Hartley-Asp, B., Estramustine depolymerizes microtubules by binding to tubulin Cancer Research 1993, 53 (19), 4573-4581 74 Farnsworth, N., The pharmacognosy of the periwinkles: Vinca and Catharanthus Lloydia 1961, 24, 105-138 128 75 Johnson, I S.; Armstrong, J G.; Gorman, M.; Burnett, J P., The vinca alkaloids: a new class of oncolytic agents Cancer Research, 1963, 23(8), 1390-1427 76 Kuehne, M E.; Bornmann, W G.; Markó, I.; Qin, Y.; LeBoulluec, K L.; Frasier, D A.; Xu, F.; Mulamba, T.; Ensinger, C L.; Borman, L S., Syntheses and biological evaluation of vinblastine congeners Organic & Biomolecular Chemistry 2003, (12), 2120-2136 77 Barnett, C J.; Cullinan, G J.; Gerzon, K.; Hoying, R C.; Jones, W E.; Newlon, W M.; Poore, G A.; Robison, R L.; Sweeney, M J., Structure-activity relationships of dimeric Catharanthus alkaloids Deacetyl vinblastine amide (vindesine) sulfate Journal of Medicinal Chemistry 1978, 21 (1), 88-96 78 Potier, P.; Langlois, N.; Langlois, Y.; Guéritte, F., Partial synthesis of vinblastine-type alkaloids Journal of the Chemical Society, Chemical Communications 1975, (16), 670-671 79 Zavala, F.; Guénard, D.; Potier, P., Interaction of vinblastine analogues with tubulin Experientia 1978, 34 (11), 1497-1499 80 Sundberg, R J.; Gadamasetti, K G.; Hunt, P J., Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline Spectroscopic observation and chemical reactions of intermediates Tetrahedron 1992, 48 (2), 277-296 81 Vukovic, J.; Goodbody, A.; Kutney, J.; Misawa, M., Production of 3', 4'- anhydrovinblastine: a unique chemical synthesis Tetrahedron 1988, 44 (2), 325-331 82 Sagui, F.; Chirivì, C.; Fontana, G.; Nicotra, S.; Passarella, D.; Riva, S.; Danieli, B., Laccase-catalyzed coupling of catharanthine and vindoline: an efficient approach to the bisindole alkaloid anhydrovinblastine Tetrahedron 2009, 65 (1), 312-317 83 Scott, A.; Gueritte, F.; Lee, S., Role of anhydrovinblastine in the biosynthesis of the antitumor dimeric indole alkaloids Journal of the American Chemical Society 1978, 100 (19), 6253-6255 84 Goodbody, A E.; Watson, C D.; Chapple, C C.; Vukovic, J.; Misawa, M., Extraction of 3′, 4′-anhydrovinblastine from Catharanthus roseus Phytochemistry 1988, 27 (6), 1713-1717 85 Mangeney, P.; Zo Andriamialisoa, R.; Langlois, N.; Langlois, Y.; Potier, P., Preparation of vinblastine, vincristine, and leurosidine, antitumor alkaloids from 129 Catharanthus species (Apocynaceae) Journal of the American Chemical Society 1979, 101 (8), 2243-2245 86 Kutney, J.; Siu Leung Choi, L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C., A highly efficient and commercially important synthesis of the antitumor Catharanthus alkaloids vinblastine and leurosidine from catharanthine and vindoline Heterocycles 1988, 27 (8), 1845-1853 87 Shirahama, T.; Kohno, T.; Kaijima, T.; Nagaoka, Y.; Morimoto, D.; Hirata, K.; Uesato, S., Stereoselective conversion of anhydrovinblastine into vinblastine utilizing an anti-vinblastine monoclonal antibody as a chiral mould Chemical and Pharmaceutical Bulletin 2006, 54 (5), 665-668 88 Ishikawa, H.; Colby, D A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T J.; Hwang, I.; Boger, D L., Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues Journal of the American Chemical Society 2009, 131 (13), 4904-4916 89 Kuehne, M E.; Matson, P A.; Bornmann, W G., Enantioselective syntheses of vinblastine, leurosidine, vincovaline and 20'-epi-vincovaline The Journal of Organic Chemistry 1991, 56 (2), 513-528 90 Magnus, P.; Mendoza, J S.; Stamford, A.; Ladlow, M.; Willis, P., Nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analog: Solvent effect on the stereochemistry of the crucial C-15/C18'bond Journal of the American Chemical Society 1992, 114 (26), 10232-10245 91 Mangeney, P.; Andriamialisoa, R.; Lallemand, J.-Y.; Langlois, N.; Langlois, Y.; Potier, P., 5'-Nor anhydrovinblastine: Prototype of a new class of vinblastine derivatives Tetrahedron 1979, 35 (18), 2175-2179 92 Andriamialisoa, R.; Langlois, N.; Langlois, Y.; Potier, P., Composés antitumoraux du groupe de la vinblastine: nouvelle méthode de préparation Tetrahedron 1980, 36 (20-21), 3053-3060 93 Guéritte, F.; Pouilhes, A.; Mangeney, P.; Andriamialisoa, R.; Langlois, N.; Langlois, Y.; Potier, P., Composes antitumoraux du groupe de la vinblastine: derives de la nor-5'anhydrovinblastine European journal of Medicinal Chemistry 1983, 18 (5), 419-424 130 94 Reddy, P., Organofluorine Compounds in Biology and Medicine," Organofluorine Compounds in Biology and Medicine Elsevier Inc, 2015, 293 95 Racemic total syntheses: (a) Ando, M., Buechi, G., and Ohnuma, T., Total synthesis of (±)-vindoline, Journal of the American Chemical Society 1975, 97, 68806881; (b) Kutney, J.P., Bunzli-Trepp, U., Chan, K.K., De Souza, J.P., Fujise, Y., Honda, T., Katsube, J., Klein, F.K., and Leutwiler, A., Total synthesis of indole and dihydroindole alkaloids 14 A total synthesis of vindoline, Journal of the American Chemical Society 1978, 100, 4220-4224; (c) Andriamialisoa, R.Z., Langlois, N., and Langlois, Y., A new efficient total synthesis of vindorosine and vindoline, The Journal of Organic Chemistry., 1985, 50, 961-967; Enantioselective total syntheses: (a) Feldman, P.L and Rapoport, H., Synthesis of (–)-vindoline, Journal of the American Chemical Society., 1987, 109, 1603-1604; (b) Kuehne, M.E., Podhorez, D.E., Mulamba, T and Bornmann, W.G., Biomimetic alkaloids syntheses 15 Enantioselective syntheses with epichlorohydrin: total syntheses of (+)-, (–)- and (±)-vindoline and a synthesis of (–)-vindorosine, The Journal of Organic Chemistry., 1987, 52, 347-353; (c) Kobayashi, S., Ueda, T., and Fukuyama, T., An efficient total synthesis of (–)-vindoline, Synlett, 2000, 2000(06), 883-886; (d) Ishikawa, H., Elliott, G.I., Velcicky, J., Choi, Y., and Boger, D., Total synthesis of (–)- and ent-(+)-vindoline and related alkaloids, Journal of the American Chemical Society., 2006, 128(32), 10596-10612 96 Moisan, L.; Thuéry, P.; Nicolas, M.; Doris, E.; Rousseau, B., Formal Synthesis of (+)‐Catharanthine Angewandte Chemie International Edition 2006, 45 (32), 53345336 97 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T., Stereocontrolled total synthesis of (+)-vinblastine Journal of the American Chemical Society 2002, 124 (10), 2137-2139 98 Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T., Stereocontrolled total synthesis of (+)-vincristine Proceedings of the National Academy of Sciences of the United States of America 2004, 101 (33), 11966-11970 99 Miyazaki, T.; Yokoshima, S.; Simizu, S.; Osada, H.; Tokuyama, H.; Fukuyama, T., Synthesis of (+)-vinblastine and its analogues Organic Letters 2007, (23), 47374740 131 100 Jacobs, D I.; Snoeijer, W.; Hallard, D.; Verpoorte, R., The Catharanthus alkaloids: pharmacognosy and biotechnology Current Medicinal Chemistry 2004, 11 (5), 607-628 101 O'Connor, S E.; Maresh, J J., Chemistry and biology of monoterpene indole alkaloid biosynthesis Natural Product Reports 2006, 23 (4), 532-547 102 El-Sayed, M.; Verpoorte, R., Catharanthus terpenoid indole alkaloids: biosynthesis and regulation Phytochemistry Reviews 2007, (2-3), 277-305 103 Caputi, L.; Franke, J.; Farrow, S C.; Chung, K.; Payne, R M.; Nguyen, T.-D.; Dang, T.-T T.; Carqueijeiro, I S T.; Koudounas, K.; de Bernonville, T D., Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle Science 2018, 360 (6394), 1235-1239 104 Pearce, H L., Chapter Medicinal Chemistry of Bisindole Alkaloids from Catharanthus In The Alkaloids: Chemistry and Pharmacology, Brossi, A.; Suffness, M., Eds Academic Press, 1990, 37, 145-204 105 Borman, L S.; Kuehne, M E., Functional hot spot at the C-20’position of vinblastine In The Alkaloids: Chemistry and Pharmacology, Elsevier, 1990, 37, 133144 106 Armstrong, J G.; Dyke, R W.; Fouts, P J.; Hawthorne, J J.; Jansen, C J.; Peabody, A M., Initial clinical experience with vinglycinate sulfate, a molecular modification of vinblastine Cancer Research 1967, 27 (2 Part 1), 221-227 107 Rao, K S B.; Collard, M P M.; Dejonghe, J P C.; Atassi, G.; Hannart, J A.; Trouet, A., Vinblastin-23-oyl amino acid derivatives: chemistry, physicochemical data, toxicity, and antitumor activities against P388 and L1210 leukemias Journal of Medicinal Chemistry 1985, 28 (8), 1079-1088 108 Lavielle, G.; Hautefaye, P.; Schaeffer, C.; Boutin, J A.; Cudennec, C A.; Pierre, A., New alpha.-amino phosphonic acid derivatives of vinblastine: chemistry and antitumor activity Journal of Medicinal Chemistry 1991, 34 (7), 1998-2003 109 Adenis, A.; Pion, J.-M.; Fumoleau, P.; Pouillart, P.; Marty, M.; Giroux, B.; Bonneterre, J., Phase II study of a new vinca alkaloid derivative, S12363, in advanced breast cancer Cancer Chemotherapy and Pharmacology 1995, 35 (6), 527-528 110 Ramnath, N.; Schwartz, G N.; Smith, P.; Bong, D.; Kanter, P.; Berdzik, J.; Creaven, P J., Phase I and pharmacokinetic study of anhydrovinblastine every weeks 132 in patients with refractory solid tumors Cancer Chemotherapy and Pharmacology 2003, 51 (3), 227-230 111 Butler, M S., Natural products to drugs: natural product-derived compounds in clinical trials Natural Product Reports 2008, 25 (3), 475-516 112 Shao, Y.; Zhang, H.-K.; Ding, H.; Quan, H.-T.; Lou, L.-G.; Hu, L.-H., Synthesis and Structure− Activity Relationship Studies of Cytotoxic Anhydrovinblastine Amide Derivatives Journal of Natural Products 2009, 72 (6), 1170-1177 113 Li, W.; Shao, Y.; Hu, L.; Zhang, X.; Chen, Y.; Tong, L.; Li, C.; Shen, X.; Ding, J., BM6, a new semi-synthetic vinca alkaloid, exhibits its potent in vivo anti-tumor activities via its high binding affinity for tubulin and improved pharmacokinetic profiles Cancer Biology & Therapy 2007, (5), 787-794 114 Fahy, J., Modifications in the upper or velbenamine part of the vinca alkaloids have major implications for tubulin interacting activities Current Pharmaceutical Design 2001, (13), 1181-1197 115 Voss, M E.; Ralph, J M.; Xie, D.; Manning, D D.; Chen, X.; Frank, A J.; Leyhane, A J.; Liu, L.; Stevens, J M.; Budde, C.; Surman, M D.; Friedrich, T.; Peace, D.; Scott, I L.; Wolf, M.; Johnson, R., Synthesis and SAR of vinca alkaloid analogues Bioorganic & Medicinal Chemistry Letters 2009, 19 (4), 1245-1249 116 Wolf, M A.; Johnson, R K.; Xie, D.; Avrutskaya, A.; Mullin, R.; Godfrey, B.; Mead, M A.; Trachet, E E.; Leopold, W R.; Guzzo, P., ALB‐109564, a novel tubulin inhibitor with improved efficacy over vinorelbine, is better tolerated when dosed iv versus ip, leading to improved activity in human tumor xenograft studies Molecular Cancer Therapeutics 2009, (12 Suppl), C232 117 Gotoh, H.; Duncan, K K.; Robertson, W M.; Boger, D L., 10′-Fluorovinblastine and 10′-fluorovincristine: synthesis of a key series of modified Vinca alkaloids ACS Medicinal Chemistry Letters 2011, (12), 948-952 118 Chen, S.-H.; Hong, J., Novel tubulin-interacting agents: a tale of Taxus brevifolia and Catharanthus roseus-based drug discovery Drugs of the Future 2006, 31 (2), 123150 119 Gherbovet, O.; Coderch, C.; García Alvarez, M a C n.; Bignon, J r m.; Thoret, S.; Martin, M.-T r.; Guéritte, F o.; Gago, F.; Roussi, F., Synthesis and biological 133 evaluation of a new series of highly functionalized 7′-homo-anhydrovinblastine derivatives Journal of Medicinal Chemistry 2013, 56 (15), 6088-6100 120 Gherbovet, O.; Coderch, C.; García Alvarez, M a C n.; Bignon, J r m.; Thoret, S.; Guéritte, F o.; Gago, F.; Roussi, F., One-pot synthesis of Vinca alkaloids– phomopsin hybrids Journal of Medicinal Chemistry 2014, 57 (12), 5470-5476 121 Ngo, Q A.; Roussi, F.; Cormier, A.; Thoret, S.; Knossow, M.; Guénard, D.; Guéritte, F., Synthesis and biological evaluation of vinca alkaloids and phomopsin hybrids Journal of Medicinal Chemistry 2008, 52 (1), 134-142 122 Ngo, Q A.; Roussi, F.; Thoret, S.; Guéritte, F., Elaboration of simplified vinca alkaloids and phomopsin hybrids Chemical Biology & Drug Design 2010, 75 (3), 284294 123 Roussi, F.; Guéritte, F.; Fahy, J., The vinca alkaloids Anticancer agents from natural products 2011, 2, 177-198 124 Leggans, E K.; Duncan, K K.; Barker, T J.; Schleicher, K D.; Boger, D L., A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20′ urea derivatives Journal of Medicinal Chemistry 2012, 56 (3), 628-639 125 Allemann, O.; Brutsch, M.; Lukesh III, J C.; Brody, D M.; Boger, D L., Synthesis of a potent vinblastine: rationally designed added benign complexity Journal of the American Chemical Society 2016, 138 (27), 8376-8379 126 Sheng, L X.; Da, Y X.; Long, Y.; Hong, L Z.; Cho, T P., Synthesis and biological evaluation of C-12′ substituted vinflunine derivatives Bioorganic & Medicinal Chemistry Letters 2008, 18 (16), 4602-4605 127 Gherbovet, O.; La Spisa, F.; Thoret, S.; Alvarez, M C G.; Levaique, H.; Bignon, J.; Roussi, F., Synthesis and biological evaluation of C-13′ substituted 7′-homoanhydrovinblastine derivatives Bioorganic & Medicinal Chemistry Letters 2015, 25 (8), 1771-1773 128 Sears, J E.; Boger, D L., Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure–function properties Accounts of Chemical Research 2015, 48 (3), 653-662 134 129 Hardouin, C.; Doris, E.; Rousseau, B.; Mioskowski, C., Selective deoxygenation of leurosine: concise access to anhydrovinblastine The Journal of Organic Chemistry 2002, 67 (18), 6571-6574 130 Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A., Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines JNCI: Journal of the National Cancer Institute 1991, 83 (11), 757-766 131 Thái Khắc Minh, Lê Minh Trí, Trần Thành Đạo Nghiên cứu khả liên kết mức độ phân tử dẫn chất chrysin cyclooxygenase-2 mơ hình mơ tả máy tính Tạp chí Dược học 2006, 46(6), 19-23 132 Rarey, M.; Kramer, B.; Lengauer, T., Multiple automatic base selection: Protein– ligand docking based on incremental construction without manual intervention Journal of Computer-Aided Molecular Design 1997, 11 (4), 369-384 133 Schulz-Gasch, T.; Stahl, M., Binding site characteristics in structure-based virtual screening: evaluation of current docking tools Journal of Molecular Modeling 2003, (1), 47-57 134 McMartin, C.; Bohacek, R S., QXP: powerful, rapid computer algorithms for structure-based drug design Journal of Computer-Aided Molecular Design 1997, 11 (4), 333-344 135 Schnecke, V.; Kuhn, L A., Virtual screening with solvation and ligand-induced complementarity In Virtual Screening: An Alternative or Complement to High Throughput Screening?, Springer, 2000,171-190 136 Cormier, A.; Marchand, M.; Ravelli, R B.; Knossow, M.; Gigant, B., Structural insight into the inhibition of tubulin by vinca domain peptide ligands EMBO reports 2008, (11), 1101-1106 137 Lê Phong, Tổng hợp nghiên cứu hoạt tính sinh học số ketone α,β- khơng no có cấu trúc tương tự thiên nhiên Luận án Tiến sĩ Hóa học, 2016 138 Lee, J C.; Bae, Y H.; Chang, S.-K., Efficient alpha-Halogenation of Carbonyl Compounds by N-Bromosuccinimide and N-Chlorosuccinimde Bulletin-Korean Chemical Society 2003, 24 (4), 407-408 139 Potier, P., Synthesis of the antitumor dimeric indole alkaloids from catharanthus species (vinblastine group) Journal of Natural Products 1980, 43 (1), 72-86 135 140 Szántay, C.; Balázs, M.; Bölcskei, H., Synthesis of vinca alkaloids and related compounds Part LVI 15′, 20′-Anhydrovinblastine borane complex Structural investigations using NMR methods Tetrahedron 1991, 47 (7), 1265-1274 141 Kutney, J.; SIU LEUNG CHOI, L.; Tsukamoto, H., Flavine coenzyme mediated photooxidation of 3', 4'-anhydrovinblastine Further information on the later stages of bisindole alkaloid biosynthesis Heterocycles 1988, 27 (8), 1827-1836 142 Andrews, C W.; Wisowaty, J.; Davis, A O.; Crouch, R C.; Martin, G E., Molecular modeling, NMR spectroscopy, and conformational analysis of 3′, 4′‐ anhydrovinblastine Journal of Heterocyclic Chemistry 1995, 32 (3), 1011-1017 143 Bau, R.; Jin, K K., Crystal structure of vinblastine Journal of the Chemical Society, Perkin Transactions 2000, (13), 2079-2082 144 Mangeney, P.; Langlois, N.; Leroy, C.; Riche, C.; Langlois, Y., Rearrangement of catharanthine.(V) 21-Cyanocatharanthine The Journal of Organic Chemistry 1982, 47 (22), 4261-4264 145 Danieli, B.; Palmisano, G.; Gabetta, B.; Martinelli, E M., Tabernaelegantinines C and D, two new bisindole alkaloids containing a cyano group from Tabernaemontana elegans stapf Part Journal of the Chemical Society, Perkin Transactions 1980, 601606 146 Kam, T.-S.; Yoganathan, K., Lahadinines A and B, new cyano-substituted indole alkaloids from Kopsia pauciflora Phytochemistry 1997, 46 (4), 785-787 147 Arai, T.; Takahashi, K.; Nakahara, S.; Kubo, A., The structure of a novel antitumor antibiotic, saframycin A Cellular and Molecular Life Sciences 1980, 36 (9), 1025-1027 148 Hayashi, T.; Noto, T.; Nawata, Y.; Okazaki, H.; Sawada, M.; Ando, K., Cyanocycline A, A new Antibiotic Taxonomy of the Producing organism, Fermentation, Isolation and Characterization The Journal of Antibiotics 1982, 35 (7), 771-777 149 Hayashi, T.; Nawata, Y., X-Ray crystallographic determination of the molecular structures of the antibiotic cyanocycline A and related compounds Journal of the Chemical Society, Perkin Transactions 1983, (3), 335-343 150 Fleming, F F.; Yao, L.; Ravikumar, P.; Funk, L.; Shook, B C., Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore Journal of Medicinal Chemistry 2010, 53 (22), 7902-7917 136 151 Rool, P., Vinca-alkaloid derivatives and preparation method U.S Patent 6,365,735, 2002 152 Bettiol, J L.; Sundberg, R J., Regioselective addition of organozinc reagents to 5, 6-dihydropyridinium ions and synthetic equivalents Factors effecting 1, 2-versus 1, 4-selectivity The Journal of Organic Chemistry 1993, 58 (4), 814-816 153 Sundberg, R J.; Bettiol, J.-L.; Gadamasetti, K G.; Marshalla, M.; Kelsh, L., A new approach to synthesis of vinblastine analogs Addition of organozinc reagents to the dihydropyridinium ion generated by fragmentative coupling to catharanthine and vindoline Bioorganic & Medicinal Chemistry Letters 1994, (16), 1999-2004 154 Sundberg, R J.; Hunt, P J.; Desos, P.; Gadamasetti, K G., Oxidative fragmentation of catharanthine by dichlorodicyanoquinone The Journal of Organic Chemistry 1991, 56 (5), 1689-1692 155 Vilches-Herrera, M.; Werkmeister, S.; Junge, K.; Börner, A.; Beller, M., Selective catalytic transfer hydrogenation of nitriles to primary amines using Pd/C Catalysis Science & Technology 2014, (3), 629-632 156 Ram, S.; Ehrenkaufer, R E., Ammonium formate in organic synthesis: a versatile agent in catalytic hydrogen transfer reductions Synthesis 1988, 1988 (02), 91-95 157 Heinzman, S W.; Ganem, B., Mechanism of sodium borohydride-cobaltous chloride reductions Journal of the American Chemical Society 1982, 104 (24), 68016802 158 Caddick, S.; Judd, D B.; de K Lewis, A K.; Reich, M T.; Williams, M R., A generic approach for the catalytic reduction of nitriles Tetrahedron 2003, 59 (29), 54175423 159 Bölcskei, H.; Szantay, C.; Mák, M.; Balázs, M.; Szántay, C., New Antitumor Hydroxymethyl Derivatives of Vinblastine ChemInform 1999, 30 (5) 160 Osby, J O.; Heinzman, S W.; Ganem, B., Studies on the mechanism of transition-metal-assisted sodium borohydride and lithium aluminum hydride reductions Journal of the American Chemical Society 1986, 108 (1), 67-72 161 Chung, S.-K., Selective reduction of mono-and disubstituted olefins by sodium borohydride and cobalt (II) The Journal of Organic Chemistry 1979, 44 (6), 1014-1016 162 Alotaibi, N.; Cloutier, L.; Khaldoun, E.; Bois, E.; Chirat, M.; Salvan, D., Criteria for admission of odontogenic infections at high risk of deep neck space infection 137 European Annals of Otorhinolaryngology, Head and Neck Diseases 2015, 132 (5), 261264 163 Moudi, M.; Go, R.; Yien, C Y S.; Nazre, M., Vinca alkaloids International Journal of Preventive Medicine 2013, (11), 1231 164 Gidding, C.; Kellie, S.; Kamps, W.; De Graaf, S., Vincristine revisited Critical Reviews in Oncology/Hematology 1999, 29 (3), 267-287 165 Detrich, H W.; Parker, S K.; Williams, R C.; Nogales, E.; Downing, K H., Cold adaptation of microtubule assembly and dynamics structural interpretation of primary sequence changes present in the α-and β-tubulins of antarctic fishes Journal of Biological Chemistry 2000, 275 (47), 37038-37047 166 Ngo, Q A.; Nguyen, L A.; Vo, N B.; Nguyen, T H.; Roussi, F.; Nguyen, V T., Synthesis and antiproliferativeactivity of new vinca alkaloids containing an α, βunsaturated aromatic side chain Bioorganic & Medicinal Chemistry Letters 2015, 25 (23), 5597-5600 167 Jean-Decoster, C.; Brichese, L.; Barret, J.-M.; Tollon, Y.; Kruczynski, A.; Hill, B T.; Wright, M., Vinflunine, a new vinca alkaloid: cytotoxicity, cellular accumulation and action on the interphasic and mitotic microtubule cytoskeleton of PtK2 cells AntiCancer Drugs 1999, 10 (6), 537-543 168 Bonfil, R D.; Russo, D M.; Binda, M M.; Delgado, F M.; Vincenti, M., Higher antitumor activity of vinflunine than vinorelbine against an orthotopic murine model of transitional cell carcinoma of the bladder Urologic Oncology: Seminars and Original Investigations 2002, (4), 159-166 169 Zucker, R M.; Whittington, K.; Price, B J., Differentiation of HL‐60 cells: Cell volume and cell cycle changes Cytometry Part A 1983, (6), 414-418 170 Kolomeichuk, S N.; Terrano, D T.; Lyle, C S.; Sabapathy, K.; Chambers, T C., Distinct signaling pathways of microtubule inhibitors–vinblastine and Taxol induce JNK‐dependent cell death but through AP‐1‐dependent and AP‐1‐independent mechanisms, respectively The FEBS journal 2008, 275 (8), 1889-1899 138 PHỤ LỤC 139