Microtubules are one of the major targets for anticancer drugs because of their role in cell proliferation and migration. However, as anticancer drugs targeting microtubules have side effects, including the death of normal cells, it is necessary to develop anticancer agents that can target microtubules by specifically acting on cancer cells only. In this study, we identified chemicals that can act as anticancer agents by specifically binding to acetylated microtubules, which are predominant in triple-negative breast cancer (TNBC). The chemical compounds disrupted acetylated microtubule lattices by interfering with microtubule access to alpha-tubulin acetyltransferase 1 (αTAT1), a major acetyltransferase of microtubules, resulting in the increased apoptotic cell death of MDA-MB-231 cells (a TNBC cell line) compared with other cells, such as MCF-10A and MCF-7, which lack microtubule acetylation. Moreover, mouse xenograft experiments showed that treatment with the chemical compounds markedly reduced tumor growth progression. Taken together, the newly identified chemical compounds can be selective for acetylated microtubules and act as potential therapeutic agents against microtubule acetylation enrichment in TNBC.

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Obesity is defined as a condition of abnormal or excessive fat accumulation in adipose tissues. Deposition of triglycerides (TG) in skeletal muscle and the liver is associated with insulin resistance, especially deposition in the liver is related to nonalcoholic steatohepatitis. 1 Diacylglycerol acyltransferase (DGAT) catalyzes the terminal step in the triacylglycerol synthesis through the esterification of diacylglycerol. DGAT has been characterized two isoforms, DGAT-1 and DGAT-2, in mammals. DGAT-1 is abundantly expressed in the small intestine and fat tissues, where it plays a critical role in the absorption of dietary lipid. 2 Research has shown that the DGAT-1 deficient (DGAT −/− ) mice are resistant to diet-induced obesity, exhibit improved insulin sensitivity relative to wild-type and decreased adiposity. 3 These results have led to a number of companies to look for potent DGAT-1 inhibitors for the treatment of obesity and related metabolic disease.Extensive medicinal chemistry efforts have led to the identification and development of small-molecule inhibitors of In our previous report, we disclosed a series of aminobenzimidazole derivative containing phenylcyclohexyl acetic acid moiety with a mixture of cis and trans isomer. 5 The compound 1 showed good long-term in vivo efficacy. But it displayed relatively moderate in vitro inhibitory activity for human and mouse cell assays with IC 50 values of 112 and 568 nM, respectively.These results prompted us to further optimization of the aminobenzimidazole to enhance DGAT-1 in vitro inhibitory activity. According to Pfizer's patent, transconfiguration showed more favorable in vitro activity. 6 Also, trans-configuration of compound 1 showed two-fold more potent than compound 1 (racemic, data not shown). Therefore, we attempted to identify potent benzimidazole derivatives with trans-phenylcyclohexyl acetic acid moiety. Herein, we describe the optimization of biphenyl aminobenzimidazole derivatives with trans-phenylcyclohexyl acetic acid as DGAT-1 inhibitors (Figure 1).The trans-benzimidazole derivatives were prepared as the method depicted in Scheme 1. Commercially available 4-(4-hydroxyphenyl)cyclohexan-1-one (2) was converted to trans-methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate (3) according to known method. 7 Protection of hydroxy group with trifluoromethanesulfonic anhydride to give triflate 4 and subsequently hydrogenation of triflate 4 by using 10% palladium on carbon in methanol provided phenylcyclohexyl acetate 5. Formylation of phenylcyclohexyl acetate 5 using a Lewis acid (TiCl 4 ) and dichloromethyl methyl ether provided aldehyde 6. Further aldehyde 6 was cyclized with 4-nitro-o-phenylenediamine in the presence of oxidating agent at room temperature to give the nitrobenzimidazole 7, followed by hydrogenation provided aminobenzimidazole 8. EDCI coupling of aminobenzimidazole 8 with diverse biphenyl carboxylic acids followed by saponification of corresponding esters 9a-n provided the final acids 10a-n.The synthesized compounds were evaluated for in...

Reduction O 0220Reducing Characteristics of Metal Diisobutyl-t-butoxyaluminum Hydrides for Tertiary Amides. -LiAlH(iBu) 2 (O-tBu) and NaAlH(iBu) 2 (O-tBu) appear are excellent reagents for the partial reduction of tertiary amides to aldehydes (II) (9 examples) under mild conditions. -(CHOI, S. J.; LEE, K. J.; LEE, G. B.; AN*, D. K.; Bull.

A series of α-sulfonamido-N-adamantanecarboxamide derivatives as 11β-HSD1 inhibitors was identified.Among them, compound 7j was the most active with an IC 50 value of 8 nM in humans 11β-HSD1.Compound 7j exhibited reasonable stability, permeability and safety profiles (CYP and hERG). Compound 7j showed good ex vivo 11 β-HSD1 inhibition with~80% inhibition after 20 MPK oral dosing.Med. Chem. Commun. This journal is