TAPCMHOAHOC
DOI: l0.IS625m66-7144.2016-316
54(3)343-348 THANG 6 NAM 2016
NGHIEN CCrU T 6 N G HOP CAC HYBRID MOI C O A ARTEMISININ VOl ZIDOVUDIN (AZT) Le Huy Hah, Vi Biili Tien, Hoang Xnau Tieu, Tran Khic Vu'
Vi4n Ky thugt Hda hgc. Truing Bgi hgc Bdch khga Ha Ngi Din Tfta soan 19-02-2016; Chip nhin ding I0.<-20I6
P * sjwteiB of new hybrids of aitemisinb widi zidovndin (AZT) was described via six-step procedure Firsdv die leamon of daydroaitemisnun (2) wifli NaN, in die presence of (CH,),SiCl and a caalytic amount of Kl m CH,c'l, at ice »aw BujaatOT gave 10/teidoartemisinin (4). This compound was dien hydrolysed by PhjP m THF/H,0 at 65
? , 5 l l 5 «»™sh lO^aatomemisinin (5). Next, dK reaction of 5 widi anhydride dicacboxyUcs (anhydride glutaric 3>dmaM anlvdn* ghaanc) m Ox presence of DMAP gave new intermediates 7.,b. Compound 6 was obtSied b^
Z J 2 S ^ f „ ! ! ? L ' ^ " ^ '™»"»=*>'l " ^ •" CH,C1, m die presence of EDC and DMAP at ambient 2 " ^ ^ foUo«d by dB Ij-drob^is in CH^l,«lOH - 9:1 using NaOH 0.2 N. Fmally, die reaction of 6 and 7.,b wnh AZT m a « a , nsmg EDC and DMAP as a catalytic system affoided novel hybrids 8»* m modeiate yields The smioures of synbesized compounds were confirmed based on specttoscopic mcflMds: m, NMR and HRMS.
Keywords. Aitemistnin, dibydroartemislnin, aitemedier, aiteedier, sodium azide, hybrid.
I.DATVANDE lOsic nhu 5-fluorouraoil [7, 8], cisplatin [9], ,_ . . . „ . , . . , paclitaxel [10]. Ngoii ra, cic nghien cuu/n vifro vi Aitemsmm (1) la mpt sesquitecpen lacton chiet m vivg cho diiy AZT cftn c4 tic dpng ching ung Uiu mil Or c ^ tfianh hao hoa ving (Artemisia annua L.) v i [11]. HmSng nghien cuu cic hpp chit lai hfta dupe su dpng bm nguyen lifu dau quan ttpng cho dang Uiu hut dupc quan tam nghien ciu tt«n dil gifti
^ n ^ e n c u u kham phi Uiuoc sot ret [I]. Mpt sft [12-15]. Cic nghien ciu gin diy cho Uiiy mpt hpp hpp chat tan tong hpp co hopl tinh khing sot i^t chit Uiuftc lai hfta (chua nhifn Uiinh phin boat tinh) nhu: arttmedKr (3.), arteedier (3b) vi artesmmt (3c) eft Uil lim ting hifu Ipc vi ttong mpt si ttuong hop (hmh 1) dupc ban timg hpp tu dOiydroartemisuiin co Uil ttanh dupc sp khing Uiuftc so vfti Uiulc mpt S .'^,'7!'^Jl"^ ^ •''"^ """S '"=" "ri 1™ ^ 6 * ^ PhSn [12, 13]. Ngoii ra, Uiulc lai hfta eft Ull u 'rp'\':.^ day.cac Uiu nghifm lam sing cftn lam cho chl dp dilu tti don giin hon vi giim nguy cho diay nhieu din xuat cua artemismm Uie hifn mpt ca nrong tic Uiulc. Lien quan din vin di niy ^ so hoat nnh sinh hpc khic nhu: boat tinh khing u, eft dil dupc xem nhu li mpt chat giin giao' quan
^ !!™?.™ ?. " ^ ™ " 9''^ ™™ <'!<:'> [61- ttpng, Uiich hpp dl CO Ull xay dpng nen cic hpp chit Zidpvudm (AZT) la mpt din xuit nucleoside, dupc lai hfta ciu ttic mfti. Trong chuong ttinh tun kilm
^ k ' ^ T ' """^ * " ' * *™ '^ ' ^ ° ' ' ^ ^ * " ™*" "^^ hpp chit mfti CO tic dpng khing mig Uiu chung
„ ,X ™ l » " so bfnh giy bfti virus nhu viem tfti tap Bung vio vifc Uiift ke, tftng hpp cic din xuft m B. Oan day, AZT dupc s i dpng nhu mpt lifu mfti tien co sft khung artemisinin. Bii bio nay gifti phap dieu ttl ung Uiu dai tting tien ttien khi dupc su diifu vifc tftng hpp mpt sft hpp chit lai hfta mfti cua dgng ka hpp vm mpt so tac nhin khing ung Uiu artemisinin vfti AZT.
, _ . e.R"COCH,CH,COO«i
Hmh I: Mpt so dan xuit cua artemismm
TCHH, 54(3), 2016 2.THycNGHl5M
Dihydroartemismui (DHA) mua tu cong ty Dupc khoa, Truong Dai hpc Dupc Hi Npi. Cac tic nhin vi dung mot phin ing mua cia hing Merck vi Aldrich.
Diem chiy dupc do tren miy Electrothermal IA 9200 Shnnadzu. Pho 'H NMR vi "C NMR dupc do ttin miy Bniker AVANCE 500 MHz tai Vifn Hfta hpc, s i dpng dung moi do: CDCI3 vi DMS0-d6. Dp chuyen dich hfta hpc (S) tinh bang ppm so voi chat chuan (TMS). Hing si tuong tic (J) dupc bilu diln bing Hz. Tien trinh phin ung dupc theo doi bfti sic ky Iftp mong (TLC) s i dpng ban nhom tting sin (Merck 60 F254). Bin mftng hifn miu bing thuoc Uii vanillm trong axit sunfiiric. Sic ky cpt s i dpng silica gel eft hat 40-230 mesh.
Tdng hgp 10fl-Azidgarlemisinin(4) Mpt hon hpp cia dyhidroartemisinin (2) (2,84g, 0,01 mol, leq), sodium azide (0,98 g, 0,015 mol, 1,5 eq), KI (83 mg, 0,5 mmol, 0,05 eq) vi (CHi),SiCl (d
= 0,85, 2,54 ml, 2eq) ttxing dung mfti CH2CI2 dupc Iim lanh ft nhift dp nuftc di vi khuiy ttong 2,5 gift.
Phin ing dupc tiieo dSi bing sic k^ Iftp mftng vfti hf dung moi ttiln khai («-hexan:etyl axetat = 10:1).
Hin hpp phin ihig sau dft dupc chiet, tmng hfta vfti NaHCO] v4 I4m khan bing Na2S0,, cat Ioai dung mfti Uiu dupc cin phin ung. Sic ky cpt silica gel vfti hf dung mfti (n-hexan:etyl axetat = 90:1) Uiu dupc 10/-azidoartemisinin (4) (2,5 g, 81 %). Tinh Uil miu tting: dne: 41-43 °C. 'H NMR (500 MHz, CDCIj) 6: 5,53 (s, IH, H-12); 5,37 (d, J= 4,0 Hz, IH, H-10)- 2,71 (m, IH); 2,40-2,33 (m, IH); 2,06-2,03 (m, IH)-
1,91-1,86 (m, IH); 1,82-1,81 (m, IH); 1,89-1,87 (m IH); 1,82-1,76 (m, IH); 1,72-1,63 (m, 2H); 1,52- 1,47 (m, 2H); 1,44-1,42 (m, 3H); 1,37-1,34 (m, IH);
1,26-1,22 (m, IH); 0,96-0,90 (m, 6 H). '=C NMR (125 MHz, CDCl,) S: 104,4 (C-12); 91,8 (C-3)- 88 6 (C-12a); 80,6 (C-10); 52,5; 44,1; 37,3; 36,2; 34 5- 30,2; 25,9; 24,6; 23,5 (C-14); 20,3 (C-15); 13,1 (C- 16).
Tdng hgp lOfi-amingarlemisinin (5) Mft hon hpp gom: lO^-azidoartemisinin (4) (1,9 g, 6,15 mmol, leq), PhjP (2,417 g, 9,2 mmol, lis e^), H2O (15 ml) ttong dung moi THF (10 ml) dun hoi luu vi khuiy tiong 6 gift. Phin ing dupc dieo dfti bing sic ky Iftp mong vfti hf dung moi ttien khai CCH2Cl2:MeOH - 8:1). Hon hpp phin ing sau do dupc chiet vfti CHiCIj vi nuorc. Pha hiiu co dupc tich ra, lim khan bing NajSO, khan, co quay dufti ip suat^ giam Uiu dupc cin phin ing. CJn sau do dupc de lanh vi riia nhieu lan vfti bin hpp dung moi n-hexan:etylaxetat (10:1) dl loai bo PhjPO diu dupc lO^-aminoartemisinin (5) (1,067 g, 61 %), dupc s i
" : 1
ly^ Kh^ VSvdcgng S|r!J dpng luon cho buftc tiep theo.
TiSng hgp cdc ddn xuat lOp-aminoartemisinin chia mgch axit (7a,b)
Quy trinh chung chung tSng hgp chat 7a,b:
Mpt hon hpp gim; lO^-aminoartemisinin (5) (500 mg, 1,78 mmol, 1 eq), anhydrid glutaric hay 3,3-dimelyl anhydrid glutaric) (1,2 eq) vi DMAP (104,4 mg, 0,89 mmol, 0,5 eq) ttong CH2CI2 (10 mL) dupc khuiy ft nhift dp phong trong 8 gift. Phin ung dupc theo dfti bing sic ky Iftp mftng vfti hf dung mfti ttiln khai (CH2Cl2:MeOH - 9:1). Hftn hpp phin ung sau dft dupc chill vi lim khan bing Na2S0,, cat loai dung mfti thu dupc c§n phin ing.
Sic ky cpt silica gel thu din?c sin phim li cic axit lO/^-Ammoartemisiuin-Soxopentanoic axit (7a): Hifu suit 78 %, chit diu; Rf =• 0,50 (DCM:MeOH- 10:0,5); IR (fihn, cm'): 3298 (OH, NH), 2929, 2866 (CH, CH;), 1705 (C-O). 'NMR (500 MHz, CDCI3) 8 (ppm): 6,81 (m, IH, -NH), 5,42 (s, IH, H-12), 5,36 (t, J - 10,5 Hz, IH, H-10), 2,43-2,37 (m, 4H, H-9, H-4a, H-3"), 2,35-2,30 (m, 2H, H-l"), 2,05-2,00 (m, l a H-4p), 2,01-1,95 (m, 2H, H-2"), 1,91-1,87 (m, 2H, H-8a, H-5a), 1,78- 1,71 (m, IH, H-8P), 1,62-1,57 (m, IH, H-7P), 1,52- 1,42 (m, 2H, H-8a, H-SP), 1,40 (s, 3H, H-14), 1,38- 1,33 (m, IH, H-6), 1,30-1,24 (m, IH, H-5a), 1,05- 1,00 (m, IH, H-7a), 0,97 (d,J= 6,5 Hz, 3H, H-15), 0,85 (d, y= 7,0 Hz, 3H, H-16). " c NMR (125 MHz, CDClj) 6 (ppm): 176,2 (COOH), 172,8 (CON), 104,5 (C-3), 91,8 (C-10), 80,6 (C-12), 76,2 (C-I2a), 51,7 (C-5a), 45,6 (C-8a), 37,3 (C-1"), 36,3 (C-6), 35,3 (C-4), 34,1 (C-7), 32,6 (C-3"), 30,9 (C-9), 25,9 (C-14), 24,6 (C-5), 21,3 (C-8), 20,4 (C-2"), 20,3 (C-15), 13,1 (C-16). ESI-HRMS Um Uiiy: m/z 392.21749; Iy thuylt: C2„Hj2NO, [M+H]*:
392,21788.
10^-Aminoarteiiii5inin-33-dimetyl-5- oiopentanoic axit (7b): Hifu suit 84 %, chit diu;
Rf= 0,52 (DCM:MeOH = 10:0,5); IR (film, cm''):
3302 (OH, NH), 2937, 2885 (CH, CHj), 1717 (C-O). 'H NMR (500 MHz, CDCIj) 6 (ppm): 6,74 ( d , y - 9,5 Hz, IH, -NH), 5,43 (s, IH, H-12), 5,36(t, -'= 10,0 Hz, IH, H-10), 2,51 (d,y= 13,0 Hz, IH, H- 3'), 2,45-2,34 (m, 4H, H-K, H-9, H-4a), 2,29 (d, J' 13,5 Hz, IH, H-3'), 2,07-2,02 (m, IH, H-4p), 1,94- 1,89 (m, IH, H-8a), 1,91-1,88 (m, IH, H-5a), 1,82- 1,74 (m, 2H, H-SP), 1,65-1,61 (m, IH, H-7p), 1,54- 1,45 (m, 2H, H-8a, H-5p), 1,42 (s, 3H, CHj, H-14), 1,38-1,35 (m, IH, H-5a), 1,32-1,26 (m, IH H-6), 1,17 (s, 3H, CHl), 1,13 (s, 3H, CH,), 1,08-1,0 (m, IH, H-7a), 0,99 (d,y= 6,5 Hz, 3H, H-15), 0,89(d„/
= 7,0 Hz, 3H, H-16). "C NMR (125 MHz, CDClj) 5 (ppm): 173,3 (COOH), 173,2 (CON), 104 4 (C-3)
TCHH, 54(3), 2016
91,7 (C-10), 80,3 (C-12), 76,4 (C-12a), 51,7 (C-5a), 47,2 (C-r), 46,4 (C-3-), 45,5 (C-8a), 37,3 (C-6), 36,2 (C-4), 34,0 (C-7), 32,4 (C-2'), 29,2 (C-9), 29,1 PCHj), 25,9 (C-14), 24,6 (C-5), 21,6 (C-8), 20,2 (C- 15), 13,1 (C-16). ESI-HRMS: tim diiy: m/z 426.24910; ly Uiuylt: C22H,6NO, [M-l-H]*:
426.24918.
Tdng hop lOfi-ammoartemisinin-8-oxooclanoic axil (6): Mpt hon hpp cua 10^-aminoartemisinin (5) (500 mg, 1,78 mmol, 1 eq), suberic axit monometyl este (400 mg, 2,13 mmol, 1,2 eq), EDC (133 mg, 1,2 eq) vi DMAP (141 mg, 0,89 mmol, 0,5 eq) ttong CH2CI2 (10 mL) dugc khuiy ft nhift dp phong ttong 4 gift. Phin ing dupc theo doi bing sic ky Iftp mong vfti hf dung moi ttiln khai (CH2Cl2:MeOH - 8:2).
Hon hpp phin iing sau dft dirpc chiet lin lupt vfti nuoc, HCl 3 % va nuftc. Pha hiiu co dupc lim khan bing Na2S0,, co quay thu dupc can. Can phan img sau do dupc diuy phan bing NaOH 0,2N trong dung mfti CH2Cl2:EtOH ti If 9:1 ft nhift dp phong trong thfti gian 8 gift. Phin ung dupc theo doi bing TLC vfti hf dung mfti ttiln khai (CH2Cl2:MeOH = 7:3).
Hftn hpp phin ing sau do dupc bl sung CHjCL, chiet vfti H2O. Pha nuftc sau dft dupc axit hfta bing HCl 0,2 N loi pH = 7, chiit vfti CH2CI2. Pha huu co dupc tach ra va lam khan bing Na;SO,. co quay dufti ap suit giim, sic ky cpt silica gel hf dung moi (CH2Cl2:MeOH = 9:1) thu dupc sin phira 10^- aminoartemisinin-8-oxooctanoic acid (6): Hifu suit 80 %, chat diu R, = 0,53 (DCM:MeOH = 15:0,5); IR (film, cm'): 3299 (OH, NH), 2921,2868 (CH.'cHj) 1699 (C=0). 'H NMR (500 MHz, DMSO-d.) 6 (ppm): 11,9 (s, IH, OH), 8,49 (d, 7 = 9,0 Hz IH NH), 5,40 (s, IH, H-12), 5,08 (t, J- 4,0 Hz, IH, H- 10), 2,31-2,26 (m, IH, H-9), 2,16-2.12 (m, 3H, H-6', H-4ii), 2,09-2,05 (m, IH, H-4p), 1,99-1,96 (m, 4H, H-8a, H-5a, H-l'), 1,82-1,78 (m, IH, H-SP), 1,63- 1,60 (m, IH, H-7P), 1,51-1,43 (m, 6H, H-2' H-5' H-8a, H-SP), 1,38-1,31 (m, IH, H-6), 1,26-1,23 (m,' 7H, H-3', H-4', H-14), 1,18-1,12 (m, IH, H-5a) 0,80-0,92 (m, IH, H-7a), 0,89 (d, 7= 6,0 Hz, 3H H- 15), 0,71 (d, y = 7,0 Hz, 3H, H-16). '=C NMR (125 MHz, DMSO-ds) 8 (ppm): 174,5 (COOH), 172 3 (CON), 103,3 (C-3), 90,6 (C-IO), 80,1 (C-12) 75 1 (C-12a), 51,4 (C-5a), 45,1 (C-8a), 36,1 (C-1'), 36,'o (C-6), 35,3 (C^), 33,7 (C-7), 33,6 (C-6'), 31,6 (C- 9), 28,3 (C-3', C-4'), 25,6 (C-14), 24,9 (C-2') 24 4 (C-5), 24,3 (C-8), 24,2 (C-5'), 20,1 (C-15), 12,9 (C- 16). ESI-HRMS tim Uiiy m/z: 440.26478- ly diuylt- CjjHjiNO, [M-l-H]*: 440.26426.
Ting hgp cdc hgp chdt Iai hda ctia artemisinin vdi AZT(8a-c)
Nghien tneu tdng hop cdc hybrid...
Quy trinh chung:
Mpt hftn hpp gftm: din xuit 10- aminoartemisinin chiia mpch axit (6, 7a,b) (1 eq), AZT (1,1 eq), EDC (1,1 eq) vi DMAP (0,5 eq) Oxing CH2CI2 (10 mL) dupc khuiy ft nhift dp phong trong 5 gift (15 gift vfti 6). Ph4n ung dupc Uieo doi bing sac ky Iftp mftng vfti hp dung mfti tiiin khai (CH2Cl2:MeOH = 7:2). Hftn hpp phin ung sau dft dupc chiet va lam khan bing Na2S04, cit Ioai dung mfti UIU dupc can phin ung. Sic icy cpt silica gel thu dupc san pham hybrid 8-c.
Hpp chit 8a. Hieu suit 41 %, dilm chay 111,3- 113.4 °C: 'H NMR (500 MHz, CDCl,) 8 (ppm): 7,21 (s, IH, CH<:), 6,32 (d, y = 9,5 Hz, IH, NH), 6,06 (m, IH, H-r). 5,41 (s, IH, H-12), 5,34 (t, 7 = 10,0 Hz, IH, H-10), 5,30 (s, 3H), 4,39 (dd, ./ = 4 5 Hz, 12.0 Hz, lH).4,34(dd,y=3,5 Hz, 12 Hz. 1H).228 (q, J = 6,0 Hz, IH), 4,06 (dd. J = 3.5 Hz. 12 Hz.
IH). 1,93 (s, 3H, CH,). 1,90-1,86 (m, 2H), 1,77-1,72 (m, 3H), 1,61-1.56 (m, IH), 1,50-1,43 (m, 2H) l.41(s, 3H, H-14). 1,37-1,34 (m. IH). 1.29-1,23 (m 2H). 1.03-0.99 (m. IH). 0.97 (d, J- 6,0 Hz, 3H, H- 15), 0.84 (d. 7 . 7,5 Hz 3H, H-16). '=C NMR (125 MHz, CDCIj) 5 (ppm): 172,6 (COO). 171.8 (CON) 163.5 (CON). 135.8 (C-C). 111.3 (C-C). 1044 (C- 3) 91,7 (C-10). 86.1 (C-12), 81.8 (C-12a). 80.5 (C- 1'); 76.0 (C-4'); 63.1 (C-5'). 60.5 (C-3'). 51.7 (C- 5a), 45.6 (C-8a). 37.4 (C-2'). 37,3 (C-6), 36,3 (C-4) 35.1 (C-I"), 34.1 (C-7), 32.7 (C-3"). 26.0 (C-14).
24.6 (C-5). 21,7 (C-8), 20.4 (C-2"), 20.2 (C-15).
13,1 (CH,). 12.6 (C-16). ESI-HRMS tim thiy m/z:
647,30301; ly thuylt: CmHuNsOio ^M-^H1*
647,30407.
Hpp chat 8b. Hifu suit 38 %; chat diu- 'H NMR (500 MHz, CDCl,) 5 (ppm): 8,60 (s, 1H, NH) 7,28 (s, IH. CH=C); 6.42 (m. IH. IH, H-I), 5.38 (s IH. H-12). 5.30 (s. IH); 5.29 (t,J. 10.0 Hz, IH, H- 10). 4.43 (dd. y = 4.5 Hz. 12 Hz, IH), 4,29 (dd, J- 3,0 Hz, 12 Hz, IH), 4.25 (q, J - 6,5 Hz. IH), 4,08 (m, 1H), 2,66 (d, 7 = 14,5 Hz, IH), 2,45 (t, y = 6 5 Hz, 2H). 2.42 (d. J= 2.0 Hz. IH). 2.39 (s. IH), 2.36- 2.31 (m. 1H). 2,22 (s. y = 4.0 Hz. 1H). 2.04-1.99 (m, IH). 1.95 (s, 3H. CH,). 1.90-1.86 (m, IH), 1,76-1 71 (m, 2H), 1,59-1,55 (m, IH), 1,49-1,41 (ra, 2H), I 39 (s, 3H, H-14), 1,37-1,32 (m, IH), 1,28-1,23 (m, IH), 1.15 (s. 6H, 2CHj). 1,02-0,99 (m, IH), 0,97 (d, 7 - 6,0 Hz, 3H, H-15), 0,83 (d, 7 = 7,0 Hz, 3H, H-16)
"C NMR (125 MHz, CDCl,) 5 (ppm): 171,8 (COO) 171,0 (CON), 163,4 (CON), 149,9 (CON), 135 9 (C=C), 111,3 (C=C), 104,3 (C-3), 91,6 (C-10), 85^8 (C-12), 81,8 (C-12a), 80,4 (C-l), 75,8 C-4'), 63,1 (C-5'), 60,5 (C-3'), 51,7 (C-5a), 46,8 (C-8a), 45 7 (C-1"), 44,4 (C-3"), 37,3 (C-6), 36,3 (C-4), 34,I(C- 7), 33,1 (C-2"), 25,9 (C-14, 2CH,), 24,6 (C-5), 21 6
TCHH, 54(3), 2016
(C-7), 20,2 (C-15), 13,2 (CH,), 12,6 (C-16). ESI- HRMS tim Uiiy m/z: 675,33302; ly Uiuyet:
CjiHiNiOiofM-i-H]*: 675,33537.
Hpp chat 8c. Hifu suit 43 %; chat dau; 'H NMR (500 MHz, CDCl,) 8 (ppm): 8,80 (s, IH, NH), 7,22 (s, IH, CH-C), 6,11 (m, IH, H-l'), 5,42 (s, IH, H-12), 5,35 (t, J= 10,5 Hz, IH, H-10), 5,30 (s, 2H), 4,40 (dd, y= 4,5 Hz, 12,0 Hz, IH), 4,31 (dd, 7 = 3,0 Hz, 12,5 Hz, IH), 4,22 (m, IH), 4,09 (A,J= 4,0 Hz, IH), 2,50-2,46 (m, IH), 2,39-2,32 (m, 5H), 2,21- 2,17 (m, 2H), 2,04-2,01 (m, IH), 1,94 (s, 3H, CH,), 1,89-1,87 (m, IH), 1,75-1,71 (m, 4H), 1,64-1,58 (m, 511), 1,50-1,45 (m, 2H), 1,41 (s, 3H, H-14), 1,34 (brs, 5H), 1,30-1,26 (m, IH), 0,97 (i,J= 6,5 Hz, 3H, H-15), 0,85 (d, J= 7,5 Hz, 3H, H-16). "C NMR (125 MHz, CDClj) 8 (ppm): 173,0 (COO), 172,1
Tran Khac i/il vd c^gs^k (CON), 163,0 (CON), 150,0 (CON), 135,6 (C=C)t1 111,2 {C=C), 104,3 (C-3), 91,7 (C-IO), 85,6 (C-I2X '•
81,8 (C-12a), 80,4 (C-I'). 75,9 (C-4'), 63,1 (C-5'), 60,7 (C-3'), 53,4; 51,7 (C-5a), 45,6 (C-8a), 37,5 (C- 6), 37,3 (C-1"), 36,3 (C-4). 34,1 (C-7), 33,9 (C-6"X 28,7 (C-3"); 28,6 (C-4"), 25,9 (C-14); 25,0 (C-2", i C-5"), 24,6 (C-5), 21,6 (C-7), 20,2 (C-15), 13,1 i (CH,), 12,6 (C-16). ESI-HRMS tun Uiay m/z. \ 689,35136; ly Uiuyet C,jH„N(0,o[M-fHl*J '
689,35102. • 3. KET QUA VA T H A O LUAN
Qua trinh ting hpp cic din xuat 10-ammo- artemisinin lai hfta vfti AZT dupc minh hpa nhu ft sp dft 1 vi2.
8 ^ 8A"
I",
.oa„
t i . 'KI^CH C?" n V ' ' ^ , ™ - T^ff^.t"i • " " ' * " " " " '"•'^ * ' " ''i«" ™ * "^^"^ « (CHj),SiCI,
^ , ;• KI . ' j J ', • ?'"• *' ^'' <"^ ^^'^' THMjO, 65 °C, 6 gift, 61 %%; (iii) anhydrid glutaric 3,3-dimetyI anhydrid gl^.«inc, EDC DMAP, CH2C2, 8 gift; 38-52 •/, (iv) suberic axi{ m o n ™ e ? e '
CH2Cl2,4gio;(v)CH2Cl2/MeOH(9:I),NaOH0,2N,8gi4,55%
Truftc het, cic din xuit mfti ti^ng gian 10- aminoartemisinin chia mach nhinh axit 6 vi 7a,b dupc ting hpp (so do 1). Dihydroartemisinin (2) dupc phin ing vfti NaN, su dpng tac nhin axit Lewis, (CH3),SiCI va mpt lupng nhft xuc tic KJ.
Phin ing dupc Uipc hifn ttong dung moi CH2CI2 ft nhift dp nuftc di ttong 2,5 gift Uiu dupc sin phim chinh li lO^-azidoartemisinin (4) sau khi tich cpt [16, 17]. Phin ling cia chit niy vfti tic nhan PhjP ttong hf dung mfti THF/H2O ft 65 "C tiong Uifti gian 8 gift Uiu dupc sin phim 10^-aminoartemisinin [16].
Cic hpp chat 7a,b Uiu dupc qua phin ung cia 4 vfti anhydrid glutiuic va 3,3-dimetyl anhydrid glutaric sft dpng hf xuc tic EDC, DMAP ttong dung mfti CH2CI2. Hpp chat 6 dupc dilu chl qua 2 buftc. Buftc
1 li phin ing cua 5 vfti suberic axit monometyl este ttong sp CO mil cua hf xuc tie EDC, DMAP ttong dung mfti CH2CI2 ft nhift dft phftng ttong 8 gift. Hin hpp phan ung sau dft dupc chiit lin lupt vfti nuftc, HCl 5 % vi NaHCO, 5 % dl Uiu dupc 5a di sach di Uipc hifn cho phin ung tilp Uieo. Hpp chit 5a sau dft dupc ttiiy phin ttong hon hpp dung mfti CH2Cl2/MeOH (9:1) su dpng NaOH 0,2 N. Phin ing xiy ra^gan nhu ttjin lupng [18]. Ciu ttiic cia cac hpp chat tiling gian chua mach nhinh axit dupc khing dinh ttfn co sft cia cic phi: IR, NMR vi ESI- HRMS. Hpp chit « dupc su dpng lim vl dp dl . ching minh ciu tiic cia diy cic chit tiimg gian <
7a,b Uiu dupc. Pho ' H NMR cho Uiiy diy di tin hifu cua cic prottm Bong phin tii, ttong dft tin hifu
TCHH, 54(3), 2016 Nghien cuu long hgp cdc hybrid..
T^ S'n u " ' " ? " ^ ™ ' ' * '™*"S * ^ ' • ' " PP"" tt l ^ a " sit dupc ft 5,40 ppm.
•1 9,0 Hz), tin hifn ^inolpt ntii. tnmn ,.,;,. r.,;^ is i i hifu singlet d i e tnmg c i a c i a H-12
9 , s CH, 0 = L „ J 0 . 0 ^ . . ^ S
'Y<^°-V^
8a-c linker a. -CHzCHjCHi-
b. -CHjClCHJaCHr 1" 2- J '
-CHiCHiCHjCHjCHiCHr Sodd 2: T i n g hpp cac hybrid 8a-c: dilu kifn va t i c nhin: AZT. EDC. DMAP. CH2CI,. nhift'dp phftng
12 gio vol chat 8a.b; 15 gift vfti chit Sc Tin hifu dublet (J= 4.0 Hz) ft 5.08 ppm la cua
H-IO. Ngoii ra, cac tin hifu dfc trung khic c i a khung anemisinin nhu cac nhftm metyl ft vi tti 14 va 15 quan sit dupc dufti dpng c i c dublet ft 0,89 (d, J ' 6,0 Hz) v i 0,71^ ppm (d, J = 7,0 Hz). Phft ' ' c NMR cung cho diay s p eft mat cua d i y d i tin hifu cia cac bon ttong phin tii. C i c tin hifu 4 174,5;
172,3 ppm tirong i n g vfti cacbon cacbo.xylic v i cac bon amit. Cac chuyen dich hfta hpc ft 103,3; 90.6;
80,1 ppm tuorng i n g vfti c i c c i c bon dac tnmg ft C-I, C-12 v4 C-IO c i a khung artemisinui. C u l i c u n g can ttiic cua hpp chit nay dupc khing dinh qua pho khoi lupng phan giii cao. Phft ESI-HRMS cho Uiiy pic [M-l-H]* m/z: 440,26478 mong i n g vfti cong dlftc phin tii C2iH„N0,.
Cic hpp chit mfti cua artemisinin Iai hfta vfti AZT 8a-c dupc tftng hpp nhu ft so dft 2. C i c hpp chat chua mpch nhinh axit 6, 7a,b thu dupc ft tten dupc cho phin i n g voi AZT tt^mg dung mfti CH2CI2 ft nhift dp phftng ttong 12-15 gift tinng su eft mil c i a hf x i c t i c EDC, DMAP cho mpt loat cac hybrid mfti mong muln 8a-c vfti hifu suit kha. Phft 'H v4 C c i a cic chit lai hfta deu eft sp xuat hifn c i a c i c proton v i cacbon die trung cua nhin diymin v i phin duftng c i a nua AZT gin v i o . Cuoi c i n g ciu ttic c i a cic hybrid mfti tong hpp 8a-c dupc dupc khing dinh qua pho NMR v i ESI-HRMS.
4. KET LUAN
D i tong hpp mpt so hpp chit mfti hybrid c i a atteraismin vfti AZT Uiong qua c i c hpp chit ttung
gian l i cac din xuit moi cua anemisinin c h i a mpch nhinh SUA.
Loi c i m on. Cong tr'mh ndy dugc hodn thanh vii su Idi trg cita Quy Khoa hgc Cdng nghe Qudc gia (NAFOSTED) quo de tdi md so 104.01-2013 01.
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?: Tran Kb^c Vu Vi?n Ky thugt H6a hpc Truang Dgi hpc Bach khoa Ha Npi So 1, Dgi C6 Vi^t, Hai Bk Trung, Ha Npi
E-mail: [email protected]; Di^n tho^i: 0904306925.
