title: Ethyl-2-amino-pyrrole-3-carboxylates are novel potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest, and effectively inhibit soft tissue cancer cell growth in vitro.
abstract: Microtubules are known to be one of the most attractive and validated targets in cancer therapy. However, the clinical use of drugs that affect the dynamic state of microtubules has been hindered by chemoresistance and toxicity issues. Accordingly, the development of novel agents that target microtubules is needed. Here, we report the identification of novel compounds with pirrole and carboxylate structures: ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) that provide potent cytotoxic activities against multiple soft tissue cancer cell lines in vitro. Using the MTS cell proliferation assay, we assessed the activity of EAPCs on various cancer cell lines including leiomyosarcoma SK-LMS-1, rhabdomyosarcoma RD, gastrointestinal stromal tumor GIST-T1, A-673 Ewing's sarcoma, and U-2 OS osteosarcoma. We found that in the majority of cases, two EAPC compounds (EAPC-20 and EAPC-24) considerably inhibited cancer cell proliferation in vitro. The growth-inhibitory effects of EAPC-20 and EAPC-24 were time and dose dependent. The molecular mechanisms of action of these compounds were because of the inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to considerable accumulation of tumor cells in the M-phase. Finally, EAPCs induced tumor cell death by apoptotic pathways. The above-mentioned effects were also observed in most soft tissue tumor cell lines and the gastrointestinal stromal tumor cell line investigated. Taken together, our data identify potent antitumor activity of EAPCs in vitro, thus providing a novel scaffold with which to develop potent chemotherapeutic agents for cancer therapy.
authors.affiliation: aDepartment of Pathology, Kazan State Medical University, Kazan bDepartment of Zootechnology, Perm State Academy of Pharmacy, Perm, Russian Federation cNevada Biomedical Research Institute, University of Nevada, Reno, Nevada, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Boichuk
authors.forename: Aigul
authors.initials: A
authors.lastname: Galembikova
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zykova
authors.forename: Bulat
authors.initials: B
authors.lastname: Ramazanov
authors.forename: Ramil
authors.initials: R
authors.lastname: Khusnutdinov
authors.forename: Pavel
authors.initials: P
authors.lastname: Dunaev
authors.forename: Svetlana
authors.initials: S
authors.lastname: Khaibullina
authors.forename: Vincent
authors.initials: V
authors.lastname: Lombardi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002264:Carboxylic Acids / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D011758:Pyrroles; D014404:Tubulin; D050257:Tubulin Modulators