Nghiên cứu tổng hợp và hoạt tính sinh học các dẫn xuất mới của alkaloid dừa cạn

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 dòng 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 dòng 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 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Catharanthus roseus Hình 1.7 Một số alkaloid dừa cạn sử dụng lâm sàng Alkaloid dừa cạn (Vinca alkaloid) họ hợp chất indole dạng dimer chiết xuất bán tổng hợp từ dừa cạn Catharanthus roseus, đại diện