Methoxy-enriched cationic stilbenes as anticancer therapeutics.

Stilbene-based compounds are largely described for their antioxidant activity. But their use as anticancer chemotherapeutics is hampered by poor pharmacokinetic properties and non-selectivity towards cancer and non-cancer potency. To overcome these drawbacks, twin chain cationic lipid conjugated, methoxy-enriched stilbene derivatives were designed, synthesized and evaluated for their anticancer potency. Our findings reveal that HMSC16, a molecule with the highest number of methoxy groups and with C16-twin chain lipid, is the most potent as well as the most selective anticancer agent when compared to the other synthesized derivatives and commercially available stilbene-based drug, tamoxifen, and resveratrol. To justify these results, we have conducted a series of mechanistic experiments where we found that HMSC16 induced ROS generation, apoptosis, and autophagy by affecting the mitochondrial, lysosomal and nuclear pathways. Further cell cycle analysis data reveals that HMSC16 not only induces cell death but is also involved in the arrest of the cell cycle at the sub-G1 phase. Moreover, HMSC16 showed self-aggregation property owing to a possibly favorable hydrophilic-lipophilic balance. The self-aggregation property of HMSC16 allowed it to entrap hydrophobic drugs, withaferin. With entrapped withaferin, HMSC16 showed additive if not synergistic cell killing effect in HeLa cells. From the above results, we concluded that HMSC16 can be used not just as a drug but also as a drug delivery agent.

Oestrogen receptor-mediated liposomal drug delivery for treating melanoma.

Function of steroid hormone oestrogen that transactivates oestrogen receptor (ER) is expressed in multiple organs. Except for malignancies of gynaecological organs, ER remains largely unutilised as a target to treat cancers of ER-expressing brain, prostate, skin etc. We have previously developed oestrogen targeting cationic lipid molecule (ES-C10), which showed targeted killing of ER + breast and skin cancer cells. In this study, we explored the targeting ability of ES-C10 as a ligand as well as its additive killing effect (if any), when incorporated in two different liposomes (DCME and DCDE), carrying two anticancer molecules MCIS3 and Docetaxel™, respectively. DCME and DCDE exhibited higher cytotoxicity in ER + cancer cells than in ER - cancer or in non-cancer cells. Both liposomes induced ER-mediated cytotoxicity and caspase 3-induced apoptosis in ER + melanoma cells. Further, decreased levels of pAkt, and increased levels of PTEN and p53 were also observed. Both the targeted liposomes were least haemolytic. These selectively delivered drug-cargoes to tumour mass over other vital organs and induced better anti-tumour effect, which led to increased survivability than their respective controls. In conclusion, we demonstrated the development of two independent liposomal drug-delivery systems associated with an anticancer, oestrogen-structure based ligand for efficient, ER-mediated anti-melanoma effect.

Cationic folate-mediated liposomal delivery of bis-arylidene oxindole induces efficient melanoma tumor regression.

The folate receptor (FR) is a well-validated and common target for cancer due to its high over-expression in many different cancer cells. Herein, we developed a new FR-targeting ligand (FA8) by conjugating folic acid and a cationic lipid. Owing to its favorable structural property FA8 as a ligand could be accommodated at an unusually higher molar ratio for a ligand-targeted liposome. We then encapsulated a drug-like molecule, bis-arylidene oxindole (NME2), in the targeted liposome. The resulting formulation induced potent caspase-8 up-regulation even in FR-moderately expressing melanoma cells. The NME2-associated non-targeted liposome (i.e., without FA8) or pristine NME2 could not up-regulate caspase-8. Caspase-8, an important apoptotic protein involved in the extrinsic pathway of apoptosis-signalling and inhibition of acquired drug resistance, was induced in cancer cells due to the combination treatment of liposomally associated FA8 and NME2 through the activation and subsequent cleavage of RIP-1. Consistently, in a melanoma tumor model too wherein FR is moderately expressed, significant tumour regression was obtained with this liposomal combination of FA8 and NME2. In conclusion, we demonstrate the development of a new FR-targeting ligand molecule whose higher level of inclusion (>10 mol%) in the liposomal formulation altered the mode of anticancer action of the encapsulated drug, thereby indicating a new therapeutic possibility involving FR targeted cancer treatment.

Ratiometric sensing of fluoride and acetate anions based on a BODIPY-azaindole platform and its application to living cell imaging.

A new BODIPY-azaindole based fluorescent sensor 1 was designed and synthesized as a new colorimetric and ratiometric fluorescent chemosensor for fluoride. The binding and sensing abilities of sensor 1 towards various anions were studied by absorption, emission and (1)H NMR titration spectroscopies. The spectral responses of 1 to fluoride in acetonitrile-water were studied: an approximately 69 nm red shift in absorption and ratiometric fluorescent response was observed. The striking light yellow to deep brown color change in ambient light and green to blue emission color change are thought to be due to the deprotonation of the indole moiety of the azaindole fluorophore. From the changes in the absorption, fluorescence, and (1)H NMR titration spectra, proton-transfer mechanisms were deduced. Density function theory and time-dependent density function theory calculations were conducted to rationalize the optical response of the sensor. Results were supported by confocal fluorescence imaging and MTT assay of live cells.

9-Acridone-4-carboxylic acid as an efficient Cr(III) fluorescent sensor: trace level detection, estimation and speciation studies.

9-Acridone-4-carboxylic acid has been established as an efficient Cr(III) fluorescent sensor. The binding of this ligand with Cr(III) is confirmed by FTIR, thermal and mass spectral analysis of the product. Based on this chelation assisted fluorescence quenching, a highly sensitive spectrofluorometric method is developed for trace level detection, estimation and speciation studies of chromium in DMF-water. The ligand has an excitation and emission maxima at 408 nm and 498.4 nm, respectively. The equilibrium binding constant of the ligand with Cr(III) is 8.1378 × 10(4) as calculated using Stern-Volmer equation. Up to 9 × 10(-6)mol L(-1) of [Cr(3+)], linearity has been observed. The interference of foreign ions has been found to be negligible.

Structure-based design, synthesis, and A-site rRNA cocrystal complexes of functionally novel aminoglycoside antibiotics: C2" ether analogues of paromomycin.

A series of 2"-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit microM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.