Sesquiterpene from Polygonum barbatum disrupts mitochondrial membrane potential to induce apoptosis and inhibits metastasis by downregulating matrix metalloproteinase and osteopontin in NCI-H460 cells.

Globally, lung cancer accounts for 18% of cancer-associated mortalities. Among the subtypes, non-small cell lung cancer (NSCLC) is the most prevalent. The increased resistance and poor survival rates signify disease aggressiveness and thus require a search for an alternative anticancer molecule. Earlier, the sesquiterpene, i.e., compound 3 ((E)-methyl 6-acetoxy-7-methoxy-1-(2-methylpropylidene)-1H-indene-3-carboxylate) from Polygonum barbatum, was isolated, characterized by us, and reported for preliminary anticancer activity. Therefore, based on these results, this study was designed to explore the underlying molecular mechanism of apoptosis and metastasis against NCI-H460 cells. The molecular mechanism of compound 3 inducing apoptosis and inhibiting metastasis was elucidated by analyzing mitochondrial membrane potential, DNA fragmentation, clonogenic assay, invasion assay, and expression of apoptotic (caspases 3, 6, 8, 9, and BAK) and metastatic markers (MMP 2, MMP 9, and osteopontin). Compound 3 significantly inhibited cell proliferation and induced apoptosis via the intrinsic route, i.e., the mitochondrial pathway, by disrupting mitochondrial membrane potential. The enhanced expression of caspases 6, 9, BAK, and HRK with downregulation of Bcl-2L1 and Ki67 further confirmed the involvement of the intrinsic apoptotic pathway. Moreover, compound 3 restricted the invasive nature of NCI-H460 cells evinced by reduced cell invasion in Boyden chamber invasion assay and downregulating the expression of metastatic markers, i.e., matrix metalloproteinase 2/9 and VEGF. It was also found to block osteopontin by negatively regulating its expression, a marker protein in cancer management. Conclusively, this sesquiterpene exhibited potent anticancer and antimetastatic activity and can be explored further as possible pharmacophores.

Natural products embedded crown ethers as potent insulin secretory agents.

Natural products embedded crown ethers were prepared by utilizing bioactive natural products including chrysin, tetrahydroisoquinoline (THIQ), and biochanin-A. The prepared crown ether scaffolds were evaluated and compared with their natural product precursors for insulin secretory activity on isolated mice islets and for their fluorescent properties. All the crown adducts were found more active as compared to their natural product precursors. Bischrysin 32-crown-10 (6d), THIQ 15-Crown-5 (6a) and chrysin 16-crown-5 (6c) showed mild, moderate and strong insulin secretory activity, respectively when compared with the standard drug tolbutamide (TB). Particularly crown derivative 6c showed strong activity (31.10 ng/islet/h) that is almost two (02) fold higher than that of standard drug TB (16.82 ng/islet/h). To the best of our knowledge crown ethers based antidiabetic study is being reported for the first time in literature through this work. Furthermore, fluorescence study showed the significant increase in absorption and emission maximum (hypsochromic effect) in crown structures when compared with their natural product precursors. Present optimistic results obtained from this study may be a guided template for developing new effective insulin secretory agents.

Apoptotic and antimetastatic activities of betulin isolated from Quercus incana against non-small cell lung cancer cells.

BACKGROUND: Globally, the prevalence and mortality rates of lung cancer have been escalated with the increasing trend of tobacco smoking. The toxicity and irresponsive nature of the available drugs for lung cancer treatment demands an alternative approach. METHODS: In this study, four known compounds namely, cirsimaritin (4',5, -dihydroxy-6,7-di-methoxyflavone) (1), eupatorin (5,3'-dihydroxy-6,7,4'-trimethoxyflavone) (2), betulin (Lup-20 (29)-ene-3, 28-diol) (3), and ß-amyrin acetate (12-Oleanen-3yl acetate) (4) have been isolated from the leaves extract of Quercus incana. Preliminary screening of these natural compounds (1-4) was performed against non-small cell lung carcinoma (NCI-H460) and normal mouse fibroblast (NIH-3T3) cell lines. RESULTS: The compounds were found to be antiproliferative against cancer cells with wide therapeutic index in comparison to the normal cells. Effects of betulin (3) on cell migration, invasion, apoptosis, and expression of important apoptosis- and metastasis-related markers were observed at different concentrations. The results showed significant dose-dependent induction of apoptosis after the treatment with betulin (3) followed by increased expression of the caspases family (ie, caspase-3, -6, and -9), proapoptotic genes (BAX and BAK), and inhibiting anti-apoptotic genes (BCL-2L1 and p53). Furthermore, wound healing and transwell invasion assays suggested that betulin (3) could also regulate metastasis by inhibiting MMP-2/-9. Osteopontin, a central regulator of apoptosis and metastasis was also inhibited in a dose-dependent manner. CONCLUSION: The present findings suggest that betulin (3) can be an attractive chemotherapeutic target for treating resistant lung cancers.

Schiff bases in medicinal chemistry: a patent review (2010-2015).

INTRODUCTION: Schiff bases are synthetically accessible and structurally diverse compounds, typically obtained by facile condensation between an aldehyde, or a ketone with primary amines. Schiff bases contain an azomethine (-C = N-) linkage that stitches together two or more biologically active aromatic/heterocyclic scaffolds to form various molecular hybrids with interesting biological properties. Schiff bases are versatile metal complexing agents and have been known to coordinate all metals to form stable metal complexes with vast therapeutic applications. Areas covered: This review aims to provide a comprehensive overview of the various patented therapeutic applications of Schiff bases and their metal complexes from 2010 to 2015. Expert opinion: Schiff bases are a popular class of compounds with interesting biological properties. Schiff bases are also versatile metal complexing ligands and have been used to coordinate almost all d-block metals as well as lanthanides. Therapeutically, Schiff bases and their metal complexes have been reported to exhibit a wide range of biological activities such as antibacterial including antimycobacterial, antifungal, antiviral, antimalarial, antiinflammatory, antioxidant, pesticidal, cytotoxic, enzyme inhibitory, and anticancer including DNA damage.