کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10585598 | 981368 | 2013 | 17 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells
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کلمات کلیدی
EDCO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphateQuantitative yieldDMT-MM4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlorideCDCl3XIAPHOBtTFADMFTHF1-ethyl-3-(3-dimethylaminopropyl)carbodiimide - 1-اتیل-3- (3-dimethylaminopropyl) carbodiimide1-hydroxybenzotriazole - 1-هیدروکسی بنزوتریازولcIAP - ciapDMSO - DMSON,N-dimethylformamide - N، N-dimethylformamidePd/C - Pd / Cethyl - اتیلAcetyl - استیلTrifluoroacetic acid - اسید TrifluoroaceticISO - ایزوTERT - تترTetrahydrofuran - تتراهیدروفورانTertiary - ترتیبDimethyl sulfoxide - دیمتیل سولفواکسیدMethyl - متیلinhibitors of apoptosis proteins - مهارکننده های پروتئین آپوپتوزیسDIPEA - نخودMelting point - نقطه ذوبHATU - هاتوPalladium on carbon - پالادیوم در کربنPropyl - پروپیل
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23Â nM and cellular IAP [cIAP]: IC50 1.1Â nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8Â nM) with high permeability and low potential of MDR1 substrate.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 24, 15 December 2013, Pages 7938-7954
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 24, 15 December 2013, Pages 7938-7954
نویسندگان
Zenyu Shiokawa, Kentaro Hashimoto, Bunnai Saito, Yuya Oguro, Hiroyuki Sumi, Masato Yabuki, Mie Yoshimatsu, Yohei Kosugi, Yasuyuki Debori, Nao Morishita, Douglas R. Dougan, Gyorgy P. Snell, Sei Yoshida, Tomoyasu Ishikawa,