To improve the potential of curcumin to treat advanced hormone-refractory prostate cancer, three series (A–C) of heteroaromatic analogs (thirty two compounds) with different monoketone linkers have been synthesized and evaluated for cytotoxicity against two human androgen-independent prostate cancer cell lines (PC-3 and DU-145). Among them, thirty analogs are more potent than curcumin against PC-3 cells, and twenty one analogs are more cytotoxic towards DU-145 cells relative to curcumin. The most potent compounds (44, 45, 51, and 52) also showed impressive cytotoxicity against three other metastatic cancer cell lines (MDA-MB-231, HeLa, and A549), with IC50 values ranging from 50 nM to 390 nM. All four most potent analogs exhibited no apparent cytotoxicity towards the MCF-10A normal mammary epithelial cells. Taken together, selective enhancement of cell death in prostate cancer cell lines and other aggressive cancer cell lines suggests that nitrogen-containing heteroaromatic rings are promising bioisosteres of the substituted phenyl ring in curcumin.

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import complex TIM23 was just recently discovered: Mgr2. Our initial analysis of protein sequence showed that, like other TIM23 subunits, Mgr2 contained GXXXG motifs in certain trans membrane domains. These motifs were implicated in subunit oligomerization and pore stability. We hypothesized that Mgr2 was a structural component of the insertion pore, and that its deletion would impair peptide import and mitochondrial functioning. We analyzed protein import in Mgr2 deficient strains using fluorescein labeled synthetic import peptides. We also tested the effect of Mgr2 deletion on mitochondrial function by measuring accumulation of fluorescent membrane potential indicators and by determining respiratory activity using a Clark-type oxygen electrode. Moreover, TIM23 function was also examined in isolated mitochondria by patch clamp electrophysiology. The results suggested that Mgr2 depletion affected the basal membrane potential and the response to depolarizing and hyperpolarizing agents. Interestingly, patch clamp analysis suggested a decrease in pore size and gating properties. Further investigation will target the role of GXXXG motifs present in Mgr2 and other TIM23 components.