Reactivity of chloroethyl sulfides in the presence of a chlorinated prophylactic: a kinetic study by EPR/spin trapping and NMR techniques†**

Arroyo, Carmen M.; Schafer, Robert J.; Carmichael, Alasdair J.

doi:10.1002/1099-1263(200012)20:1+<::aid-jat663>3.0.co;2-p

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“…In our current research, we conjugated 1,4-naphthoquinone pharmacophores with alkylating moieties, i.e., 2-chloroethylthio group, to further improve cytotoxic activity toward cancer cells. Mono- and bis(2-chloroethyl)sulfide (also known as sulfur mustard) are cytotoxic agents which exert their biological action via alkylation of guanine nucleotides in the DNA and by provoking oxidative stress [ 19 , 20 ]. At the beginning of the 20th century, bis(2-chloroethyl)sulfide and its derivatives were developed as chemical weapons.…”

Section: Introductionmentioning

confidence: 99%

Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells

et al. 2021

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Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, 30 and 32, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa.

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Section: Introductionmentioning

confidence: 99%