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.
Highlights
Nitrogen‐containing heterocycles are pharmacologically important scaffolds and are present in numerous clinically approved drugs[1–3]
The synthesized compounds were evaluated against various cancer cell lines including murine metastatic breast cancer 4T1, murine glioma GL261-luc[2], human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPaCa-2, and human colorectal adenocarcinoma WiDr
Since diarylurea based drug candidates are known to exhibit antiangiogenic properties, we further studied candidate compounds 8i and 11 for their preliminary in vitro mechanism of action
Summary
Nitrogen‐containing heterocycles are pharmacologically important scaffolds and are present in numerous clinically approved drugs[1–3]. Nitrogenous heterocycles offer a unique opportunity in drug development as they readily allow for the manipulation of lipophilicity, polarity, and hydrogen bonding[1–3]. These manipulations could potentially result in improved physiochemical properties including pharmacokinetics, pharmacodynamics, and toxicological profile to enhance efficacy of drugs[1–3]. Literature reports indicate that the indazole structural unit is utilized in numerous pharmacologically active agents including drugs with anti-cancer properties[4–6]. Diaryl ureas have recently been explored as pharmacophores for the development of anticancer agents with numerous mechanisms of action, including anti-angiogenesis[17]. Examples of diaryl urea containing anticancer agents include regorafenib and sorafenib with clinical indications for colorectal and kidney cancers, r espectively[18–23]. We have synthesized and evaluated a series of N-phenylindazolyl diarylureas derivatives as potential anticancer agents
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