2. Academic Validation
  3. A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

  • Eur J Med Chem. 2021 Mar 15:214:113229. doi: 10.1016/j.ejmech.2021.113229.
Romeo Romagnoli 1,  Paola Oliva 2,  Maria Kimatrai Salvador 2,  Stefano Manfredini 3,  Chiara Padroni 4,  Andrea Brancale 5,  Salvatore Ferla 6,  Ernest Hamel 7,  Roberto Ronca 8,  Federica Maccarinelli 8,  Fatlum Rruga 9,  Elena Mariotto 9,  Giampietro Viola 10,  Roberta Bortolozzi 11
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Chimiche, Farmaceutiche e Agrarie, Via Luigi Borsari 46, Università Degli Studi di Ferrara, 44121, Ferrara, Italy. Electronic address: rmr@unife.it.
  • 2 Dipartimento di Scienze Chimiche, Farmaceutiche e Agrarie, Via Luigi Borsari 46, Università Degli Studi di Ferrara, 44121, Ferrara, Italy.
  • 3 Dipartimento di Scienze Della Vita e Biotecnologie, Università Degli Studi di Ferrara, 44121, Ferrara, Italy.
  • 4 Medicinal Chemistry Department, Integrated Drug Discovery, Aptuit, An Evotec Company, Via A. Fleming 4, 37135, Verona, Italy.
  • 5 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
  • 6 Swansea University Medical School, Swansea, UK.
  • 7 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
  • 8 Dipartimento di Medicina Molecolare e Traslazionale Unità di Oncologia Sperimentale Ed Immunologia, Università di Brescia, 25123, Brescia, Italy.
  • 9 Dipartimento di Salute Della Donna e Del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy.
  • 10 Dipartimento di Salute Della Donna e Del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy; Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti 4, 35128, Padova, Italy. Electronic address: giampietro.viola.1@unipd.it.
  • 11 Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti 4, 35128, Padova, Italy. Electronic address: roberta.bortolozzi@unipd.it.
PMID: 33550186 DOI: 10.1016/j.ejmech.2021.113229
Abstract

Three different series of cis-restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by a palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human Cancer cell lines. In the two series of 1,2-diaryl pyrrole derivatives, results suggested that the presence of the 3',4',5'-trimethoxyphenyl moiety at the N-1 position of the pyrrole ring was more favorable for antiproliferative activity. In the series of 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal antiproliferative activity, showing excellent antiproliferative activity against the CA-4 resistant HT-29 cells. Inhibition of tubulin polymerization of selected 1,2 pyrrole derivatives (9a, 9c, 9o and 10a) was similar to that observed with CA-4, while the isomeric 3,4-pyrrole analogues 11i-k were generally from 1.5- to 2-fold more active than CA-4. Compounds 11j and 11k were the only compounds that showed activity as inhibitors of colchicine binding comparable to that CA-4. Compound 11j had biological properties consistent with its intracellular target being tubulin. This compound was able to block the cell cycle in metaphase and to induce significant Apoptosis at a concentration of 25 nM, following the mitochondrial pathway, with low toxicity for normal cells. More importantly, compound 11j exerted activity in vivo superior to that of CA-4P, being able to significantly reduce tumor growth in a syngeneic murine tumor model even at the lower dose tested (5.0 mg/kg).

Keywords

1H-pyrrole; Antimitotic agents; Antiproliferative activity; Structure-activity relationship; Tubulin polymerization.

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