title: Synthesis and SAR of 2',3'-bis-O-substituted N(6), 5'-bis-ureidoadenosine derivatives: implications for prodrug delivery and mechanism of action.
abstract: 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-N(6)-(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). IC(50) values ranged from 3.0±0.3 to >200μg/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-N(6)-(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 (K(d)=11.7±0.5μM), 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.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, United States.
authors.forename: Jadd R
authors.initials: JR
authors.lastname: Shelton
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Cutler
authors.forename: Megan S
authors.initials: MS
authors.lastname: Browning
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Matt A
authors.initials: MA
authors.lastname: Peterson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D000241:Adenosine