Synthesis and pharmacological screening of a large library of 1,3,4-thiadiazolines as innovative therapeutic tools for the treatment of prostate cancer and melanoma

• Published in: European journal of medicinal chemistry 2015-11, Vol.105, p.245-262
• Main Authors: De Monte, Celeste, Carradori, Simone, Secci, Daniela, D'Ascenzio, Melissa, Guglielmi, Paolo, Mollica, Adriano, Morrone, Stefania, Scarpa, Susanna, Aglianò, Anna Maria, Giantulli, Sabrina, Silvestri, Ida
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Eg5 inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kinesin - antagonists & inhibitors; Kinesin - metabolism; Male; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Mice; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Thiadiazolines
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.10.023

Antimitotic agents are widely used in cancer chemotherapy but the numerous side effects and the onset of resistance limit their clinical efficacy. Therefore, with the purpose of discovering more selective and efficient anticancer agents to be administered alone or in combination with traditional drugs, we synthesized a large library of 1,3,4-thiadiazoline analogues, maintaining the pharmacophoric structure of an antiproliferative compound known as K858: this is a new inhibitor of kinesin Eg5, able to induce the mitotic arrest in colorectal cancer cells and in xenograft ovarian cancer cells. We screened 103 compounds to assess their antiproliferative activity on PC3 prostate cancer cell line. Two derivatives, compounds 32 (corresponding to K858) and 33, have shown to be the most effective against prostate tumor cells and also towards two melanoma cell lines (SK-MEL-5 and SK-MEL-28) at low micromolar concentrations, confirming the pharmacological activity of this scaffold and revealing the potential role of 1,3,4-thiadiazolines in the management of cancer. [Display omitted] •A large library of 1,3,4-thiadiazolines were synthesized on the basis of K858 structure.•Some of them proved to inhibit the growth of PC3, SK-MEL-5 and SK-MEL-28 cancer cells.•Eg5 kinesin inhibitory activity was also evaluated for the most active derivatives.•Cell cycle analysis of different cancer cell lines and expression of GADPH and Cyclin D after treatment were carried out.