Synthesis, in vitro, and in vivo evaluation of novel N-phenylindazolyl diarylureas as potential anti-cancer agents

Abstract

Novel N-phenylindazole based diarylureas have been designed, synthesized and evaluated as potential anticancer agents. In vitro cell viability studies of these derivatives illustrate good potency with IC50 values in the range of 0.4–50 μM in several cancer cell lines including murine metastatic breast cancer 4T1, murine glioblastoma GL261, human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPaCa-2, and human colorectal cancer cell line WiDr. The ester group in the lead compound 8i was modified to incorporate amino-amides to increase solubility and stability while retaining biological activity. Further in vitro studies reveal that lead candidates inhibit tube length in HUVEC cells. In vivo systemic toxicity studies indicate that these candidate compounds are well tolerated in mice without any significant side effects. Anticancer efficacy studies in WiDr tumor xenograft and 4T1 tumor syngraft models demonstrate that the lead candidate 11 exhibits significant antitumor properties as a single agent in these tumor models.

Imatinib Mesylate-Loaded Rosin/Cinnamon Oil-Based In Situ Forming Gel against Colorectal Cancer Cells

“…Thus, there was no difference in the cell viability of drug-loading or drug-free ISG in vitro cell viability determination because the release compounds easily contacted with and killed the cancel cells. Nonetheless, the in vivo accessibility of drug to the environment surrounding cancer cell is more difficult than the medium in vitro test [ 73 , 74 ]. Therefore, the IM-loaded formulation should exhibit its action apparently in vivo owing to IM release with its high sensitivity to cancer.…”

Complexification of In Vitro Models of Intestinal Barriers, A True Challenge for a More Accurate Alternative Approach

“…Indeed, the Caco-2 cell line shows TEER values four times higher than HT-29. As part of the stabilized cell lines derived from HT-29, we can cite WiDr, used for tumorigenesis studies as xenografts on nude mice; HT29-MTX and HT29-18N, carrying a goblet cell phenotype when cultivated with methotrexate or carbachol, respectively; HT29-FU, being chemoresistant and generally used for carcinogenesis studies; and HT-29 18C, which may lack sucrase-isomaltase when cultivated in a medium containing glucose [ 39 , 43 , 76 ].…”

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective

“…N ‐phenyl‐4‐(3‐phenylureido)benzamide substituted at N ‐1 of indazole ( 204 ) (Figure 22) reduces angiogenesis in the cancer cell. Compound 204 also can act as histone deacetylase (HDAC) and Arora kinase inhibitor and DNA directing alkylating agent due to the presence of diaryl urea moiety with increased bioavailability (Solano et al, 2020). Direct N −1 substitution with diaryl urea moiety in indazoles ( 192 ) possesses a broad range of anticancer activities with minimal toxicity.…”