Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b was the most active compound, with IC50 values ranging from 5.7 to 10.7 µM. Molecular docking of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis (which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1 expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction, showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic activity, induces apoptosis, and targets CDK1, supporting further studies for the development of similar compounds against PDAC.
Highlights
We further investigated the bis-indolyl marine alkaloid topsentin 4, characterized by the presence of a carbonyl spacer group, which gives greater flexibility to the molecule to better adapt to the ATP-binding site of cyclin-dependent kinase 1 (CDK1) and represents a hydrogen bonding acceptor, which could interact with the amino acid residues of the active site of CDK1
Considering the promising results shown by [3-(1H-Indol-3-yl)-[1,2,4]oxadiazol-5-yl]-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3yl)-methanones 5 on Pancreatic ductal adenocarcinoma (PDAC) cancer cell lines [20], we decided to synthesize a new series of topsentin analogs of the type 6 shown in Scheme 1, in which the imidazole central ring was replaced by 1,2,4-oxadiazole moiety, and one indole portion was converted into
In the present study we efficiently synthesized a new series of 1,2,4-oxadiazole derivatives 6a–f that showed promising antiproliferative activities in vitro against a series of PDAC is one of the most lethal forms of cancer, characterized by poor survival rates of 5 years, late diagnosis, and lack of effective treatment
Summary
Camilla Pecoraro 1,2 , Barbara Parrino 1 , Stella Cascioferro 1 , Adrian Puerta 2,3 , Amir Avan 2,4 , Godefridus J. Peters 2,5 , Patrizia Diana 1 , Elisa Giovannetti 2,6, * and Daniela Carbone 1, *. BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, c/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain. Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad 91886-17871, Iran. Cancer Pharmacology Laboratory, Fondazione Pisana per la Scienza, Via Ferruccio Giovannini 13, San Giuliano Terme, 56017 Pisa, Italy. Cascioferro, S.; Puerta, A.; Avan, A.; Peters, G.J.; Diana, P.; Giovannetti, E.; Carbone, D.
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