•An efficient method for preparing the title compounds is presented.•The reaction requires only 10 min at 110–120 °C under microwave conditions.•Products were obtained in excellent yields (65–84%).•Products were obtained in analytically pure form.•Total preparation time was approx. 1 h (including isolation).Treatment of N-[(4-hydroxy-6-phenyl)pyrimidin-2-yl]cyanamide with 1° alkyl or arylamines in isopropyl alcohol for only 10 min at 110–120 °C under microwave conditions gave the corresponding N′-alkyl(aryl)guanidine derivatives in excellent yields (65–84%). Isolated yields were greatest when >1.0 equiv. of amines were employed, but excellent results were also obtained when aryl and alkylamines were reacted with a more atom-economical loading (1.0 equiv.; 70% and 72% ave. yields, respectively). Arylamines with either highly electron withdrawing substituents (e.g. CO2H) or pi-deficient heterocycles (e.g. variously substituted aminopyridines) did not work well under these conditions, and reaction with ureas and/or amino acids did not give detectable products. Work-up was exceedingly simple, and involved simple collection and washing of product on a sintered glass funnel. Products were obtained in analytically pure form and required approximately 1 h to prepare, start to finish.Download high-res image (109KB)Download full-size image

Treatment of Boc-protected N9-aryladenines with 1° alkylamines (1.1 equiv) and DMAP (1.1 equiv) in DMF at 80 °C in the presence of activated 5 Å molecular sieves gave the corresponding N6-urea derivatives in excellent yields (66–96%). Select derivatives were screened for antiproliferative activity against a panel consisting of L1210, CEM, and HeLa cells. The most potent analogue exhibited selective activity against HeLa cells (IC50 = 11 ± 1 μM).

A simple and efficient method for the preparation of 5′-O(N)-carbamyl and 5′-O(N)-polycarbamyl nucleoside derivatives is reported. The method consisted of treatment of 2′,3′-O-protected purine (Ado, Ino) or pyrimidine nucleosides (Thd, Urd) with trichloroacetylisocyanate, followed by cleavage of the trichloroacetyl moiety by silica-gel promoted methanolysis during column chromatography. Iterative application of this method gave mono, di, and tricarbamyl derivatives in good to excellent yields (ave = 80%).

A series of 2′,3′-bis-O-silylated or -acylated derivatives of lead compound 3a (2′,3′-bis-O-tert-butyldimethylsilyl-5′-deoxy-5′-(N-methylcarbamoyl)amino-N6-(N-phenylcarbamoyl)adenosine) were prepared and evaluated for antiproliferative activity against a panel of murine and human cancer cell lines (L1210, FM3A, CEM, and HeLa). 2′,3′-O-Silyl groups investigated included triethylsilyl (10a), tert-butyldiphenylsilyl (10b), and triisopropylsilyl (10c). 2′,3′-O-Acyl groups investigated included acetyl (13a), benzoyl (13b), isobutyryl (13c), butanoyl (13d), pivaloyl (13e), hexanoyl (13f), octanoyl (13g), decanoyl (13h), and hexadecanoyl (13i). IC50 values ranged from 3.0 ± 0.3 to >200 μg/mL, with no improvement relative to lead compound 3a. Derivative 10a was approximately equipotent to 3a, while compounds 13e–g were from three to fivefold less potent, and all other compounds were significantly much less active. A desilylated derivative (5′-deoxy-5′-(N-methylcarbamoyl)amino-N6-(N-phenylcarbamoyl)adenosine; 5) and several representative derivatives from each subgroup (10a–10c, 13a–13c) were screened for binding affinity for bone morphogenetic protein receptor 1b (BMPR1b). Only compound 5 showed appreciable affinity (Kd = 11.7 ± 0.5 μM), consistent with the inference that 3a may act as a prodrug depot form of the biologically active derivative 5. Docking studies (Surflex Dock, Sybyl X 1.3) for compounds 3a and 5 support this conclusion.

A preliminary library of novel N6,5′-bis-ureidoadenosine analogs and related derivatives was prepared and tested for activity against the NCI 60 panel of human cancers. A 2′-O-TBS group was found to be necessary, but not sufficient, for optimal antiproliferative activity. Neither the N6- nor 5′-ureido substituents were sufficient to achieve significant antiproliferative effects when present in the absence of the other. The 2′-O-TBS, and N6,5′-bis-ureido substitution patterns were found to be necessary for optimal antiproliferative activity.Analogs of lead antiproliferative agent 1 were prepared and tested for activities against the NCI 60 panel of human cancers. Variants in all four canonical quadrants were tested. The 2′-O-TBS, 5′-N-methylurea, and N6-phenylurea were necessary for optimal activity.