2-trifluoromethyl-2-hydroxypropion-Amide Analogues: Synthesis And Anti-cancer Studies

Inhibition of pyruvate dehydrogenase kinase (PDK), which shifts the cancer cellmetabolism from aerobic glycolysis to glucose oxidation and induces apoptosis, is anovel strategy for selective anticancer therapies. Furthermore, breast cancer resistanceprotein (BCRP)-mediated multi-drug resistance (MDR) is not only found in cancer celllines with in vitro drug treatment, but also found in clinical drug resistance, and leads tofailure of cancer chemotherapy. In this paper,2-trifluoromethyl-2-hydroxypropionamideanalogues, known as potent PDK inhibitors, were evaluated as anti-cancer agents andreversal agents of BCRP-mediated drug resistance. The main results were as follows:43anilides of N-phenyl-2-trifluoromethyl-2-hydroxypropionamide were designedand synthesized, and their anti-cancer activities were evaluated. Structure-activityrelationship (SAR) study shown that, the electron-withdrawing, bulky and hydrophobicsubstituents at the para-position were beneficial to the activity. We finally found thatN-(3-((3-aminophenyl)sulfonyl)phenyl)-3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropanamido)benzamide (compound17.27, IC50=5.39μM, H460) was potentcandidate for further drug development.11N-arylphenyl-2,2-dichloroacetamide analogues were synthesized. We found thatthese compounds and2-trifluoromethyl-2-hydroxypropionamide analogues significantlysensitized BCRP overexpressing MDR cells to their anti-cancer substrates. Compound17.11and compound26.5were two potent candidates for BCRP inhibition. They couldsensitize both wild-type and mutant BCRP overexpressing MDR cells to various BCRPsubstrates. Furthermore, they showed comparable or greater activity than the BCRPinhibitor FTC. However, they were unable to reverse P-gp or MRP7-mediated MDRindicating their selectivity for BCRP. Neither of them significantly altered BCRPprotein expression in western blotting analysis for up to72h.[3H]-mitoxantroneaccumulation study demonstrated that they increased the intracellular accumulation ofmitoxantrone. With no apparent toxicity observed in the BCRP overexpressingH460/MX20xenograft model, they enhanced the antitumor response of doxorubicin,and attenuated tumor growth.6((trifluoromethyl)sulfinyl)benzene analogues were designed and synthesized, and their anti-cancer activity was evaluated. Structure-activity relationship study shown that,sulfinyl and nitro groups were beneficial to the activity. There is not much difference inactivities of sulfoxide compounds with different halogen atoms.2-Chloro-4-nitro-1-((trifluoromethyl)sulfinyl)benzene (compound29.1) displayed potent cytotoxicityagainst19cancer cell lines, with an IC50of89nM against K562cells. When incubatedwith H460cells, compound29.1could turn the cells to apoptosis or necrosis.Monocytes proliferation assay showed that it did not significantly alter the proliferationof monocytes with the concentrations below0.12μM. Western blotting analysis wasperformed to evaluate Caspase-9expression of CEM-SS cells. It was found thatcompound29.1decreased the expression level of Caspase-9protein, which suggestedthat the induction of apoptosis was not through the up-regulation of Caspase-9.