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.
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.
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Celeste
C
De Monte
Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. Electronic address: simone.carradori@unich.it.
Simone
S
Carradori
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Daniela
D
Secci
Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Headington, Oxford, United Kingdom.
Melissa
M
D'Ascenzio
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Paolo
P
Guglielmi
Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
Adriano
A
Mollica
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena, 00185 Rome, Italy.
Stefania
S
Morrone
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena, 00185 Rome, Italy.
Susanna
S
Scarpa
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 00185 Rome, Italy.
Anna Maria
AM
Aglianò
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 00185 Rome, Italy.
Sabrina
S
Giantulli
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 00185 Rome, Italy.
Ida
I
Silvestri
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013830:Thiadiazoles; D016547:Kinesins
Antiproliferative activity; Eg5 inhibitors; Melanoma; Prostate cancer; Thiadiazolines