ABSTRACT
The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.
Subject(s)
Antineoplastic Agents/chemistry , Deoxycytidine/analogs & derivatives , Prodrugs/chemistry , Prodrugs/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Transformation, Neoplastic , Colonic Neoplasms/drug therapy , Crystallization , Crystallography, X-Ray , Cytidine/chemistry , Deoxycytidine/administration & dosage , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Humans , Mice , Models, Molecular , Molecular Conformation , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Solubility , GemcitabineABSTRACT
Structure-activity relationship (SAR) studies on the tricyclic isoxazole series of MRP1 modulators have resulted in the identification of potent and selective inhibitors containing cyclohexyl-based linkers. These studies ultimately identified compound 21b, which reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.093microM), while showing no inherent cytotoxicity. Additionally, 21b inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=0.064microM) and shows selectivity (1115-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, 21b showed tumor regression and growth delay in MRP1-overexpressing tumors in vivo.
Subject(s)
Isoxazoles/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , HeLa Cells , Humans , Isoxazoles/chemical synthesis , Kinetics , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line , Drug Screening Assays, Antitumor , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Female , Half-Life , Humans , In Vitro Techniques , Mice , Mice, Nude , Quantitative Structure-Activity Relationship , Rats , Rats, Inbred F344 , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Umbilical Veins/cytology , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor A/physiologyABSTRACT
Tricyclic isoxazoles were identified from a screen as a novel class of selective multidrug resistance protein (MRP1) inhibitors. From a screen lead, SAR efforts resulted in the preparation of LY 402913 (9h), which inhibits MRP1 and reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.90 microM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=1.8 microM). LY 402913 also shows selectivity ( approximately 22-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, LY 402913 delays the growth of MRP1-overexpressing tumors in vivo.
