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Purpose: To evaluate the efficacy and oral activity of two promising indoles, (2-(1 H-indol-3-yl)-1 H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1 H-indol-5-ylamino)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound IAT], in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. Methods: The in vitro drug-like properties, including potency, solubility, metabolic stability, and drug-drug interactions were examined for our two active compounds. An in vivo pharmacokinetic study and antitumor efficacy study were also completed to compare their efficacy with docetaxel. Results: Both compounds bound to the colchicine-binding site on tubulin, and inhibited tubulin polymerization, resulting in highly potent cytotoxic activity in vitro. While the potency of paclitaxel and docetaxel was compromised in a multidrug-resistant cell line that overexpresses P-glycoprotein, the potency of compounds II and IAT was maintained. Both compounds had favorable drug-like properties, and acceptable oral bioavailability (21-50 %) in mice, rats, and dogs. Tumor growth inhibition of greater than 100 % was achieved when immunodeficient mice with rapidly growing paclitaxel-resistant prostate cancer cells were treated orally at doses of 3-30 mg/kg of II or IAT. Conclusions: These studies highlight the potent and broad anticancer activity of two orally bioavailable compounds, offering significant pharmacologic advantage over existing drugs of this class for multidrug resistant or taxane-refractory cancers. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate abilities of 2- aryl-4- benzoyl- imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy. Methods: MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis. Results: ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg. Conclusions: This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported the discovery of 2-aryl-4-benzoyl-imidazoles (ABI-I) as potent antiproliferative agents for melanoma. To further understand the structural requirements for the potency of ABI analogs, gain insight in the structure–activity relationships (SAR), and investigate metabolic stability for these compounds, we report extensive SAR studies on the ABI-I scaffold. Compared with the previous set of ABI-I analogs, the newly synthesized ABI-II analogs have lower potency in general, but some of the new analogs have comparable potency to the most active compounds in the previous set when tested in two melanoma and four prostate cancer cell lines. These SAR studies indicated that the antiproliferative activity was very sensitive to subtle changes in the ligand. Tested compounds 3ab and 8a are equally active against highly paclitaxel resistant cancer cell lines and their parental cell lines, indicating that drugs developed based on ABI-I analogs may have therapeutic advantages over paclitaxel in treating resistant tumors. Metabolic stability studies of compound 3ab revealed that N-methyl imidazole failed to extend stability as literature reported because de-methylation was found as the major metabolic pathway in rat and mouse liver microsomes. However, this sheds light on the possibility for many modifications on imidazole ring for further lead optimization since the modification on imidazole, such as compound 3ab, did not impact the potency. [Copyright &y& Elsevier]

Toblock the metabolically labile sites of novel tubulin inhibitorstargeting the colchicine binding site based on SMART, ABI, and PATtemplates, we have designed, synthesized, and biologically testedthree focused sets of new derivatives with modifications at the carbonyllinker, the para-position in the C ring of SMART template, and modificationof A ring of the PAT template. Structure–activity relationshipsof these compounds led to the identification of new benzimidazoleand imidazo[4,5-c]pyridine-fused ring templates,represented by compounds 4and 7, respectively,which showed enhanced antitumor activity and substantially improvedthe metabolic stability in liver microsomes compared to SMART. MOMgroup replaced TMP C ring and generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Furthermodification of PAT template yielded another potent analogue 33with 5-indolyl substituent at A ring. [ABSTRACT FROM AUTHOR]