《分子对接参考文献》由会员分享，可在线阅读，更多相关《分子对接参考文献（5页珍藏版）》请在金锄头文库上搜索。
1、Synthesis and SAR of 20,30-bis-O-substituted N6, 50-bis-ureidoadenosine derivatives: Implications for prodrug delivery and mechanism of actionJadd R. Sheltona, Christopher E. Cutlera, Megan S. Browninga, Jan Balzarinib, Matt A. Petersona,aDepartment of Chemistry and Biochemistry, Brigham Young Unive
2、rsity, Provo, UT 84602-5700, United StatesbRega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgiuma r t i c l ei n f oArticle history: Received 5 June 2012 Revised 1 August 2012 Accepted 13 August 2012 Available online 21 August 2012Keywords: Purine nucleosides Bio-active adenosine de
3、rivatives Antiproliferative nucleosides BMPR1b inhibitorsa b s t r a c tA series of 20,30-bis-O-silylated or -acylated derivatives of lead compound 3a (20,30-bis-O-tert-butyldi- methylsilyl-50-deoxy-50-(N-methylcarbamoyl)amino-N6-(N-phenylcarbamoyl)adenosine) were prepared and evaluated for antiprol
4、iferative activity against a panel of murine and human cancer cell lines (L1210, FM3A, CEM, and HeLa). 20,30-O-Silyl groups investigated included triethylsilyl (10a), tert-butyldi- phenylsilyl (10b), and triisopropylsilyl (10c). 20,30-O-Acyl groups investigated included acetyl (13a), ben- zoyl (13b)
5、, isobutyryl (13c), butanoyl (13d), pivaloyl (13e), hexanoyl (13f), octanoyl (13g), decanoyl (13h), and hexadecanoyl (13i). IC50values ranged from 3.0 0.3 to 200lg/mL, with no improvement relative to lead compound 3a. Derivative 10a was approximately equipotent to 3a, while compounds13eg were from t
6、hree to fivefold less potent, and all other compounds were significantly much less active. A desilylated derivative (50-deoxy-50-(N-methylcarbamoyl)amino-N6-(N-phenylcarbamoyl)adeno- sine; 5) and several representative derivatives from each subgroup (10a10c, 13a13c) were screened forbinding affinity
7、 for bone morphogenetic protein receptor 1b (BMPR1b). Only compound 5 showed appre-ciable affinity (Kd= 11.7 0.5lM), consistent with the inference that 3a may act as a prodrug depot formof the biologically active derivative 5. Docking studies (Surflex Dock, Sybyl X 1.3) for compounds 3a and 5 suppor
8、t this conclusion. ? 2012 Elsevier Ltd. All rights reserved.As part of research directed toward the design, synthesis, and biological evaluation of potential inhibitors of HIV integrase, we discovered potent antiproliferative activities associated with a new class of N6,50-bis-ureidoadenosine deriva
9、tives exemplified by compounds 13 (Fig. 1).1IC50values for 13a (R = Ph) ranged from approximately 18lM against a majority of the human cancer cell lines in the NCI-60. IC50values for 3bi ranged from 3182lg/mL against a panel of tumor cell lines consisting of murine leukemia (L1210), murine mammary c
10、arcinoma (FM3A), human T-lympho- cyte (CEM), and human cervix carcinoma (HeLa). Preliminary SAR studies revealed that for optimal cytostatic activities (lowlM), the N6- and 50-urea moieties are required, and substitution with at least one 20(30) tert-butyldimethylsilyl (TBS) group is also neces- sar
11、y. Interestingly, compounds 5 and 6 were essentially inactive against the NCI-60 screen at 10lM concentrations. Similarly, 50-carbamates 4ai were significantly less active than the analogous 50-ureas (3ai) against L1210, FM3A, CEM, and HeLain spite of the fact that 4ai possess nearly identical subst
12、itutions as the 50- ureas.1a The above observations support the conclusion that the 20,30-O-TBS groups are necessary, but not sufficient, for biological activityand have prompted us to investigate the role of the 20,30-O-substi- tution in this class of compounds. Herein we report the synthesis and a
13、ntiproliferative activities for a series of variously substituted 20,30-O-derivatives of the most potent of these compounds (3a), and draw preliminary conclusions from the mechanistic implica- tions of this SAR study. The synthesis begins with 50-azido-50-deoxyadenosine (7) and gives 20,30-bis-O-sil
14、ylated or 20,30-bis-O-acylated products in good toexcellentyields(Scheme1).Thesynthesisisverystraightforward and is amenable to scale-up. Silylation of 7 with triethylsilylchlo- ride, tert-butyldiphenylsilylchloride, or triisopropylsilylchloride gave compounds 8ac in 4260% yield. Acylation of compou
15、nds 8ac with phenylisocyanate gave N6-phenylurea derivatives 9ac (5482%). A one-pot, two-step reaction sequence involving reduc- tion of the 50-azido group of compounds 9ac followed by acylation with the relatively safe and innocuous methylisocyanate surrogate, N-methyl p-nitrophenylcarbamate,2gave
16、10ac in 6677% yield. 20,30-Bis-O-acylated compounds 13ac and 13di were obtained via two different routes. Compounds 13ac were obtained in goodyields via a five-step protocol analogous to the one employed in preparing 10ac. However, the more lipophilic 20,30-bis-O-acylated compounds 13gi were obtained in very low yields following this procedure. An alternative route involving one step from compound5 was investigated. This route was generally much more efficient,0960
