DAI HOC QUOC GIA HA IMOI TRUdNG DAI HOC KHOA HOC TU NHIEN BAG CAO KET QUA THUC HIEN D^ TAI DAC BIET CAP DAI HOC QUOC GIA HA NOI 2001-2003 Ten de tdi: NGHIEN CIJU PHirONG PHAP TONG HOP STAVUDIN MOI LOAI THUOC CHONG HIV CO HIEU QUA HIEN NAY Mflso.QGOl-04, • '•• r Chd nhiem de tdi: GS TSKH Nguyen Dhih Trieu T^LlNGTA*^i•!1(•.' ! i N \' v mJs^ HA NOI, 2004 iirK MUC LUC I Ma dau II Tom tat ket qua chfnh _L Ket qua ve mat khoa hoc Ket qua phuc vu thuc te Ket qua dao tao Ket qua nang cao tiem luc khoa hoc Tinh hinh su dung kinh phi Abstract in Phan noi dung chfnh Dat van d^ Tong quan vi cac van de nghien cifu 2.1 Vong dai ciia HIV ; 2.2 Cac loai thudc chong HIV 2.3 Phiro'ng phap chung t6ng hop stavudin (D4T) va/idovudin (AZT) 2.4 Phuo'ng phap long hap thymidin i^huang phap nghien cu'u va kci qua 3.1 Tong hap Stavudin (D4T) va Zidovudin (AZT) 3.2 Tdng hop thymin va uraxin 3.3 Tdng hap 2'-hidroxithvmidin 3.4 Tdng hap mot sd hap chat di vong co hoat tfnh sinh hoc 3.5 Thir hoat tfnh khang khuan khang nam IV KclluAn .* 1 I 2 2 V KiC'M nghi Tai lieu tham khao Phieu dang ky ket qua nghien ciru khoa hoc 'W'nu lal c;ic cdng liliih nghien ciiii khoa hoc ciia ca nhan Phil liic Phu luc 1: Phd hdng ngoai Phu luc 2: Phd cdng hirdng lu" hat nhan I M6 DAU Ten de tai: "Nghien ctru phirang phap tdng hap stavudin, mot loai thudc chdng HIV CO hieu qua hien nay" Ma sd:QG 01-01 Caquan: Dai hoc Qudc gia Ha noi Chu tri: GS TSKH Nguyen Dinh Trieu Dan vi: Trudng Dai hoc Khoa hpc Tu nhien Cac vien: GS TSKH Nguyfin Dinh Trieu Thac sT Doan Duy Tien Thac sT Tran Thi Thanh Van Thdi gian ihirc hien: nam (tu thang 5-2001) H TOM TAT KET QUA CHINH Di tai: "Nghien cuu phuang phap tdng hgp stavudin, mot loai thudc chdng HIV co hieu quii hicn nay" Chfnh thuc dugc phe duyet la de tai dac biet cap Dai hgc Qudc gia Ha noi vao thang nam 2001 vdi thdi han 24 thang va tdng kinh phf 60 trieu ddng Den de lai da dm hoan va dat dugc nhung ket qua nhu sau: Kel qua ve mat khoa hoc • Da nghien cuu long hgp dugc V-ZO-lhymin cho 2\3'-(hdeoxy-2\3 didchidrothymin (Stavudin, D4T) Phan ung dugc tdng hgp theo hai budc buc dau lien khda nhdm chiic -OH d vi trf 5'- ciia Deoxyriboza bing Uic nhan RSO2C sau tach loai nudc bang lac nhan RONa irong dung moi ancol de lhu due stavudin (D4T) • Da nghien cuu tdng hgp dugc chat l-(3-azido-2J-dideoxy-P-[ crythropentofuianosyl) thymin (AZT) Qua trinh phan ung dugc thuc hien theo h; budc, budc dau tien can phai khda nhdm chuc -OH d C-5' cua vdn pcnlofuranoza bAng mot tac nhan khda Z-Y (nhu trityl (C(^U ^ N ,0 liude lie che ICMI men pliilu giiii diim ciia virul HIV Khi virut HIV vao dugc be bao TCD4 cila ngudi cluing sir dung loiii men phan giii diim (enzym proleaza) dugc dung cho viec long hgp protein ciui tnic loi cua virut HIN giiij) eliiiiig sinh InrcVng iiliaiih chdng Mdt sd hap chAl sau cd khii nilng lie che enzyn proleii/a ciia virul HIV : a Indiiiiivia (Indinavir) : Ten hoa hoe : | (1 S R) SS|^2.3.5-lndeo\i-N(2.3 (lihidro-2-hicIr()\i-1-II-indcn-1 yl)-5 (2[(l.l-dimclylclyl) anionoj cacbonyL4(3-pyridinylmetyl)-l-pii)erazinyI)-2 phenylmelyl]-D-erylhropcnloamil Cdng Ihiic philn 111 C^.H^nNsOf, l „ = L53- I54"C Tiic dung : lhuoc Idp hidroxiaminopentan iimit mdi Uong cac thudc lic che proteazi ciia HIV I Iil loiii thudc chdng virul b Rilonavia (Ritonavir) Ten hda hoe : |5S-(3\8R\lOR\l lR^)]10-hidroxi-2-metyl-5-(I-metyIetyI)-4 lhiazolyl)-3,6-dioxo-8,l i-bis(phenylmetyl)-2,4,7,l2-lclraiizalridecan-l 3-dioxocS.l 1- bis (phcnyimctyl)-2.4.7.12-telraiizatridecan-13-oie-thiazolylmelyl este Cdng ihii'c philn lu C.7H.,xN(,OsS2 Tiic dung : chill kieu peplit, li'c che proleaza ciia HIVi hi loai thudc chdng virul 2.2,3 Thudc uc che men chep ngugc (reversetran) Uc che enzim dd ngan chrin su tao DNA tu RNA ciia virul va dd ngiln HIV khdng gia nhap dugc vao DNA ciia vat chii vii n^m tiem An nhan te bao Thudc di1u lien ciia loai niiy hi zidovudin (AZT, Retrovir), lamivudin (Epivi, 3TC) stavudin (D4T) Trong 10 nfim qua Ciic thudc nhdm dugc sir dung nhieu nlull, diic biel hi AZT a Zidovudin (AZT, Retrovir) La diln xuat cila thymidin, cd nhdm N^ d vi trf 3' Ten hda hgc: l-(3-azido-2,3-didcoxi-P-D-erylhropcntofuranosyI)-thymih (ling ihue philn lu: C'|,,l I, iN.,()| Cdng ihirc ciTu liio: :() Tiic dung : cd hoiU tfnh chdng virut HIV rill miinh, tiVn cdng virut nd ihoiit khdi lc bao nhidm benh de nhiem triing Ciic tc bao khiic h SlaviicJin (D4T, Zeril) Ten hda hoc : 2'.3'-didchidro-3'-deoxithymidin Cdng thiic philn lu: CinHpN^Oj C Viii!' lliii'e e;lii l a o ; O CH N x> H O HO—I t,,^ : 165-166"C (dang tinh the khdng mau) Tlie dung : chdng virut, uc che enzim phien mil nguc;c Dily Iil loiii thude ed hieu quit dic^u tri HIV cao, nhill hi sii" dung ket hgp D4T/3TC/hidinavir 2.2.4 Mdt sd chill cd Uie dung ehdng HIV mdi Theo mol sd liii lieu gfin dily [16-21] mdt sd hgp chill day oxadiiizol, iriiizol hoiic disunfua cd hoiil tfnh chdng HIV nhu : o N-N II Ho' CH^—C-NH CO-N S-CFL-CO-NHAr / C.H 6'^5 CH2 CH2 CO~N \ Q1H5 2.3 Phuong phdp chung tdng hop stavudin (D4T) vd zidovudin (AZT) Plurang phiip cluing de tdng hgp D4T vil AZT, theo ciic tiii lieu cdng bd ihi deu xuitt phiii lir ihymidin Phiin ung diui ticn lii khda nhdm chuc -OH d vi trf 5'- ciia vdng p-iiboIluiinozc:f bilng ciie Uic nhiln kluie nhiui ; rdi sau dd chuyen hda ihilnh chuig (C) cd Ciiu etc: O ;A /•IL N O N 110- O o O /.-x zo- N' 0, / Cl n IN :);i/tt N- O zo- / Oil I livinidiii (/\) Oil (C) (B) Tiic nhiln khda nhdm chuc Z-X d dily cd the la: Axil pholphoric H^PO.j - Trilyl (C^J-iO^CCl AnkyI- vil arylsunfonylclorua RSO2CI Trimetylsilanclorua (CH3)^SiCI f)ieii che AZT bilng Ciich cho hgp chill C phiin ung vdi NaN^, cdn didu che stavudin cho nd phiin ling vc)i mgl chill biiza liich loiii ILO: ... thuoc chdng HIV cd hieu qua hien nay" '' MilscK " Q(i 01-01 Chii nhiem de tai: GS.TSKH Nguyen Dinh Trieu Thdi gian thuc hien: 24 thang (5/2001-5/2003) Kinh phf: 60 trieu dong Diit van de HIV- AIDS... cac ViVn de nghien ciiu 2.1 Vong dot ciia HIV[ 1-7J HIV (hiunan immimodeficicne virus) la mot retro virut cd vat lieu di truyen la RN/ (axil nbonuclcic) HIV ed khii nilng nhiem nhieu te bao limpoT,... qui trinh nhan Ien cua HIV nhat la cac enzim phien ma ngugc deu la cac dfch de thudc c Ih^ tac dong 2.2, Cdc loai thudc chdng HIV Nhung nghien ciiu vi quii trinh di6u tri HIV- AIDS cho thiiy mot