Design and evaluation of 1,2,3-dithiazoles and fused 1,2,4-dithiazines as anti-cancer agents

Kaitlyn A Maffuid; Maria Koyioni; Chad D Torrice; William A Murphy; Heemaja K Mewada; Panayiotis A Koutentis; Daniel J Crona; Christopher R M Asquith

doi:10.1016/j.bmcl.2021.128078

Design and evaluation of 1,2,3-dithiazoles and fused 1,2,4-dithiazines as anti-cancer agents

Bioorg Med Chem Lett. 2021 Jul 1:43:128078. doi: 10.1016/j.bmcl.2021.128078. Epub 2021 May 2.

Authors

Kaitlyn A Maffuid¹, Maria Koyioni², Chad D Torrice¹, William A Murphy¹, Heemaja K Mewada¹, Panayiotis A Koutentis², Daniel J Crona³, Christopher R M Asquith⁴

Affiliations

¹ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus.
³ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: chris.asquith@unc.edu.

PMID: 33951490
DOI: 10.1016/j.bmcl.2021.128078

Abstract

Heteroatom rich 1,2,3-dithiazoles are relatively underexplored in medicinal chemistry. We now report screening data on a series of structurally diverse 1,2,3-dithiazoles and electronically related 1,2,4-dithiazines with the aim of identifying interesting starting points for potential future optimisation. The 1,2,3-dithiazoles, were obtained via a number of different syntheses and screened on a series of cancer cell lines. These included breast, bladder, prostate, pancreatic, chordoma and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. Several low single digit micromolar compounds with promising therapeutic windows were identified for breast, bladder and prostate cancer. Furthermore, key structural features of 1,2,3-dithiazoles are discussed, that show encouraging scope for future refinement.

Keywords: 1,2,3-Dithiazole; Bladder cancer; Breast cancer; Chordoma; Pancreatic cancer; Prostate cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Antineoplastic Agents
Thiazoles