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

Abstract

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 ± 0.032 μM to 5.201 ± 0.125 μM by day 7 of treatment. Compared to the sodium dithiocarbamate salt 1, all the dithiocarbamate ester analogs (2 and 4a-4 g) displayed lower cytotoxicity than compound 1 (PC3, IC50 = 0.087 ± 0.005 μM; DU145, IC50 = 0.079 ± 0.003 μM and LNCaP, IC50 = 0.079 ± 0.003 μM) 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.

Iterative design of emetine‐based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy

“…In line with our earlier finding that the secondary amine of the N‐2′ position of emetine plays a crucial role in its cytotoxic activity , this present study shows that emetine could be converted to a peptidyl prodrug through its N‐2′ amine. Such prodrug could be systemically delivered for activation by cancer selective enzymes within the cancer microenvironment, such as FAP that is overexpressed by the carcinoma‐associated fibroblasts.…”

“…Recently, the cryo-EM structure at 3.2 A resolution of emetine bound to the 80S ribosome of plasmodium falciparum further highlighted the importance of the N-2′ secondary amine in stabilizing emetine–ribosome binding by forming a hydrogen bond between the NH group of the isoquinoline ring in emetine and an oxygen atom on the backbone of the protein (U2061) [14]. As part of our ongoing effort to identify emetine analogs and prodrugs with potential for reduced systemic toxicity, we have synthesized N-2′ derived analogs of emetine that are significantly less cytotoxic (i.e., ~300-fold) than emetine [15,16]. These results suggest that an N-2′ derivatized emetine prodrug could be developed.…”

Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives

“…Previously we have described prodrugs of emetine that are activatable at the relatively low pH (5.5–6.8) within the microenvironment of cancerous tumor 7 and prodrugs that are activated through sequential proteolysis by the proteases fibroblast activation protein (FAP) and (DPPIV). 9 In the present study we describe the synthesis and evaluation of a peptidyl prodrug of emetine that is activated by Prostate Specific Antigen (PSA), a serine protease selectively expressed at high levels within sites of prostate cancer.…”

Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis

“…Literature revealed that many dithiocarbamate derivatives displayed potent anticancer activity ( Figure 1 ) both in in vitro and in vivo model and might act by induction of apoptosis 6 . Molecular hybridization technique had been widely adopted in designing new dithiocarbamate cytotoxic agents which includes tetrahydrocarbazole 7 , 1,2,3-triazoles 8 , quinazolines 9 , emetine 10 , chromones 11 , benzodioxole 12 dithiocarbamate derivatives, etc 13 , 14 . However, the molecular hybridization of dithiocarbamate with bridged bicyclic compounds to achieve new class of antiproliferative agents have not been reported so far.…”