Design, synthesis, anticancer and in silico assessment of 8-piperazinyl caffeinyl-triazolylmethyl hybrid conjugates.

Autor: Soltani Rad MN; Department of Chemistry, Shiraz University of Technology Shiraz 71555-313 Iran soltani@sutech.ac.ir behrouz@sutech.ac.ir +98 71 3735 4520 +98 71 3735 4500.; Medicinal Chemistry Research Laboratory, Novel Technology for Health Research Center, Shiraz University of Technology Shiraz 71555-313 Iran., Behrouz S; Department of Chemistry, Shiraz University of Technology Shiraz 71555-313 Iran soltani@sutech.ac.ir behrouz@sutech.ac.ir +98 71 3735 4520 +98 71 3735 4500.; Medicinal Chemistry Research Laboratory, Novel Technology for Health Research Center, Shiraz University of Technology Shiraz 71555-313 Iran., Shahbazkhani K; Department of Chemistry, Shiraz University of Technology Shiraz 71555-313 Iran soltani@sutech.ac.ir behrouz@sutech.ac.ir +98 71 3735 4520 +98 71 3735 4500., Behrouz M; Department of Chemistry, Shiraz University of Technology Shiraz 71555-313 Iran soltani@sutech.ac.ir behrouz@sutech.ac.ir +98 71 3735 4520 +98 71 3735 4500., Zarenezhad E; Non-communicable Diseases Research Center, Fasa University of Medical Sciences Fasa Iran., Ghanbariasad A; Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences Fasa Iran.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2023 Aug 18; Vol. 13 (35), pp. 24656-24673. Date of Electronic Publication: 2023 Aug 18 (Print Publication: 2023).
DOI: 10.1039/d3ra04817a
Abstrakt: In this paper, we have assessed the design, synthesis, characterization, anticancer properties, toxicity, and in silico study of 8-piperazinyl caffeinyl-triazolylmethyl derivatives as new caffeine hybrid conjugates. These compounds consist of four moieties comprising 8-caffeinyl, piperazinyl, 1,2,3-triazolyl, and alkyl substituents. The synthesis of these compounds was started by bromination of caffeine to attain 8-BC, S N Ar reaction with piperazine to acquire 8-PC, N -propargylation of 8-PC and finally click Huisgen cycloaddition with diverse alkyl azides. These compounds were in vitro tested against two significant cancer cell lines comprising breast cancer MCF-7 (ATCC HTB-22) and melanoma cancer A-375 (ATCC CRL-1619) cell lines and activities compared with methotrexate (MTX) as a reference drug. Anticancer assessments indicated 12j (IC 50 = 323 ± 2.6) and 12k (IC 50 = 175 ± 3.2) were the most potent compounds against A-375 and MCF-7 cell growth, respectively and their activities were even stronger than MTX (IC 50 = 418 ± 2 for A375 and IC 50 = 343 ± 3.6 for MCF-7). Toxicities were determined by screening compounds against normal cell line HEK-293 (ATCC CRL-11268) and indicated that except 12i (IC 50 = 371 ± 2.3), 12j (IC 50 = 418 ± 2.4), and MTX (IC 50 = 199 ± 2.4), all compounds are non-toxic. Docking was conducted for 12j and 12k and determined the strong binding affinities to B-RAF kinase and hDHFR enzymes, respectively. In silico pharmacokinetic and physiochemical profiles of tested compounds were investigated which indicated that most compounds obeyed Lipinski's rule of five (RO5). The DFT study on M06-2X/6-311G (d,p) was used to indicate HOMO, LUMO, MEP, and other parameters for a better understanding of 12j and 12k reactivity. Owing to anticancer properties, toxicity, and in silico data, 12j and 12k can be proposed for further research in the future.
Competing Interests: The authors have declared no conflict of interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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