Design, synthesis and cytotoxicity studies of dithiocarbamate ester derivatives of emetine in prostate cancer cell lines

Anticancer activities of 4a to 4g in LNCaP, PC3 and DU145 prostate cancer cell lines, IC50 value ranging from 1.312±0.032μM to 5.201±0.125μM. [Display omitted] A small library of emetine dithiocarbamate ester derivatives were synthesized in 25–86% yield via derivatization of the N2′- position of eme...

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Published in:Bioorganic & medicinal chemistry 2015-09, Vol.23 (17), p.5839-5845
Main Authors: Akinboye, Emmanuel S., Bamji, Zebalda D., Kwabi-Addo, Bernard, Ejeh, David, Copeland, Robert L., Denmeade, Samuel R., Bakare, Oladapo
Format: Article
Language:English
Subjects:
Anti-cancer activities
Cell Line, Tumor
Cell Proliferation
Dithiocarbamate ester
Drug Design
Emetine
Emetine - chemical synthesis
Emetine - chemistry
Emetine derivatives
Humans
Male
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Structure-Activity Relationship
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Summary:Anticancer activities of 4a to 4g in LNCaP, PC3 and DU145 prostate cancer cell lines, IC50 value ranging from 1.312±0.032μM to 5.201±0.125μM. [Display omitted] A small library of emetine dithiocarbamate ester derivatives were synthesized in 25–86% yield via derivatization of the N2′- position of emetine. Anticancer evaluation of these compounds in androgen receptor positive LNCaP and androgen receptor negative PC3 and DU145 prostate cancer cell lines revealed time dependent and dose-dependent cytotoxicity. With the exception of compound 4c, all the dithiocarbamate ester analogs in this study showed appreciable potency in all the prostate cancer cell lines (regardless of whether it is androgen receptor positive or negative) with a cytotoxicity IC50 value ranging from 1.312±0.032μM to 5.201±0.125μM by day 7 of treatment. Compared to the sodium dithiocarbamate salt 1, all the dithiocarbamate ester analogs (2 and 4a–4g) displayed lower cytotoxicity than compound 1 (PC3, IC50=0.087±0.005μM; DU145, IC50=0.079±0.003μM and LNCaP, IC50=0.079±0.003μM) on day 7 of treatment. Consequently, it appears that S-alkylation of compound 1 leads to a more stable dithiocarbamate ester derivative that resulted in lower anticancer activity in the prostate cancer cell lines.
ISSN:0968-0896
1464-3391
1464-3391
DOI:10.1016/j.bmc.2015.06.072