کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10585782 | 981379 | 2011 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain
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کلمات کلیدی
AMPDICp-methoxybenzylCMLNAD analoguesMPAMADPMBIMPNMNinosine monophosphate dehydrogenaseAICARIMPDHinosine 5′-monophosphate - 5 "منوفسفات inosine5-Aminoimidazole-4-carboxamide riboside - 5-آمینیمیدازول-4-کاربوکامید ریبوزیدadenosine 5′-monophosphate - آدنوزین 5'-مونوفسفرهTAD - بلهTiazofurin - تیازوفورینthiazole-4-carboxamide adenine dinucleotide - تیتازول-4-کاربوکامید آدنین دیونوکلئوتیدInhibitor design - طراحی بازدارندهchronic myelogenous leukemia - لوسمی مزمن میلوئیدیmycophenolic acid - مایکوفنولیک اسید، مایکوفنولاتNAD - نادانnicotinamide adenine dinucleotide - نیکوتین آمید adenine dinucleotidenicotinamide mononucleotide - نیکوتین آمید مونونوکلئوتید
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (Ki = 5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC50 = 0.45 μM). Compound 4 was as potent as Gleevec (IC50 = 0.56 μM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with Ki's lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 5, 1 March 2011, Pages 1594-1605
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 5, 1 March 2011, Pages 1594-1605
نویسندگان
Krzysztof Felczak, Liqiang Chen, Daniel Wilson, Jessica Williams, Robert Vince, Riccardo Petrelli, Hiremagalur N. Jayaram, Praveen Kusumanchi, Mohineesh Kumar, Krzysztof W. Pankiewicz,