Anomalous 1 H NMR chemical shift behavior of substituted benzoic acid esters.

Benzoic acid esters represent key building blocks for many drug discovery and development programs and have been advanced as potent PDE4 inhibitors for inhaled administration for treatment of respiratory diseases. This class of compounds has also been employed in myriad industrial processes and as common food preservatives. Recent work directed toward the synthesis of intermediates for a proprietary medicinal chemistry program led us to observe that the 1 H NMR chemical shifts of substituents ortho to the benzoic acid ester moiety defied conventional iterative chemical shift prediction protocols. To explore these unexpected results, we initiated a detailed computational study employing density functional theory (DFT) calculations to better understand the unexpectedly large variance in expected versus experimental NMR chemical shifts.

Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells.

We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at adenine-thymine rich regions of DNA. Herein, we describe mechanistic investigations that demonstrate that this class of compounds facilitate the translocation of the ERα-compound complex to the nucleus and induce the expression of ERα target genes. We confirm that the compounds show selective toxicity in ERα-expressing cells, induce ERα localization in the nucleus, and verify the essential role of ERα in modulating the toxicity. Minor alterations in the compound structure significantly affects the DNA binding ability, which correlates to the DNA-methylating ability. These studies demonstrate the utility of DNA-alkylating compounds to accomplish targeted inhibition of the growth of specific cancer cells; an approach that may overcome shortcomings of currently used chemotherapy agents.

Synthesis, biological evaluation and docking studies of 1,2,4-oxadiazole linked 5-fluorouracil derivatives as anticancer agents.

BACKGROUND: 1,2,4-oxadiazole derivatives exhibited significant anti-cancer activity when they were evaluated, against human cancer cell lines. They also showed anti-inflammatory, analgesic, diabetic, immunosuppressive, α,ß3-receptor antagonist, antimicrobial, anti-helminthic, histamine-H3 and antiparasitic properties. A pyrimidine analog, 5 fluoro-uracil is a chemotherapeutic drug used for treating multiple solid malignant tumors. But its application is limited, as it has side effects like low bioavailability and high toxicity. Molecular docking is an exemplary tool, helps in identifying target and designing a drug containing high bio-availability and minimum toxicity. RESULTS: A set of 1,2,4-oxadiazole linked 5-fluoruracil derivatives (7a-j) were synthesized and their structures were confirmed by 1HNMR, 13CNMR and Mass spectral analysis. Further, these compounds were investigated for their anticancer activity towards a panel of four human cancer cell lines such as (MCF-7, MDA MB-231), lung cancer (A549) and prostate cancer (DU-145) by using MTT method. Among them, compounds 7a, 7b, 7c, 7d and 7i demonstrated more promising anticancer activity than standard. CONCLUSION: Synthesized derivatives (7a-j) of 1,2,4-oxadiazole linked 5-fluorouracil and investigated for their anticancer activity towards a panel of four human cancer cell lines.