Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents

• Published in: ACS combinatorial science Vol. 20; no. 12; pp. 700 - 721
• Main Authors: Semenova, Marina N, Demchuk, Dmitry V, Tsyganov, Dmitry V, Chernysheva, Natalia B, Samet, Alexander V, Silyanova, Eugenia A, Kislyi, Victor P, Maksimenko, Anna S, Varakutin, Alexander E, Konyushkin, Leonid D, Raihstat, Mikhail M, Kiselyov, Alex S, Semenov, Victor V
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2018; Amer Chemical Soc
• Subjects: Animals; Antimitotic Agents - chemical synthesis; Antimitotic Agents - pharmacology; Cell Line, Tumor; Chemistry; Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary; Drug Screening Assays, Antitumor; Embryo, Nonmammalian - drug effects; Humans; Isoxazoles - chemical synthesis; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Science & Technology; Sea Urchins - embryology; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - pharmacology; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - pharmacology; combretastatins; sea urchin embryo; diarylazoles; antimitotic; microtubule destabilization; DESIGN; POLYALKOXYBENZENES; ANTINEOPLASTIC AGENTS; CYTOTOXIC ACTIVITY; COMBRETASTATIN A-4 ANALOGS; STILBENE; BIOLOGICAL EVALUATION; 1,2,3-TRIAZOLE ANALOGS; REGIOSELECTIVE SYNTHESIS; DERIVATIVES
• ISSN: 2156-8952; 2156-8944
• DOI: 10.1021/acscombsci.8b00113

A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure–activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure–activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.