Hemisynthesis and cytotoxic evaluation of manoyl oxide analogs from sclareol: effect of two tertiary hydroxyls & Heck coupling on cytotoxicity.

Sclareol, a bioactive diterpene alcohol isolated from Salvia sclarea, was subjected to structural modification and cytotoxic evaluation. Boron-Heck-coupled analogs of manoyl oxide were prepared from sclareol in a two-step reaction scheme. In the first step manoyl oxide was prepared from sclareol using cerium (IV) ammonium nitrate. Further the structural modification of manoyl oxide via Palladium (II) catalysed Boron-Heck coupling reaction produced a new series of compounds. All the synthesised compounds were screened for in vitro cytotoxic evaluation against four cancer cell lines HCT-116, MCF-7, MDA-MB231and MDA-MB468. The results showed that manoyl oxide is less active than sclareol. Sclareol shows an IC50 of 2.0 µM compared to manoyl oxide with an IC50 of 50 µM against the MCF-7 cell line. From the results it was inferred that the presence of two tertiary hydroxyls in sclareol are necessary for its cytotoxic activity and Heck coupled analogs are more active than sclareol and manoyl oxide.

Design, synthesis and neuroprotective evaluation of nitrogen heterocyclic and triazole derivatives of sarracinic acid.

Novel sarracinic acid derivatives bearing triazole or N-heterocyclic moiety were prepared via two separate reaction schemes. The triazoles and the N-heterocyclic derivatives were synthesised using standard click chemistry approach and amination of 2-bromoethyl ester of sarracinic acid respectively. All the synthesised derivatives were screened for in vitro neuroprotective activity against corticosterone induced impairment in neuroblastoma cell line SH-SY5Y. Two analogs SA-2 and SA-12 exhibited strong neuroprotective activity. The cell viability, after high dose corticosterone induced cell death, increased remarkably with the pre treatment of SA-2 and SA-12. The in vitro biological activity of SA-2 and SA-12 was verified through docking studies. The docking studies were in good agreement with the biological results. SA-2 and SA-12 showed strong binding affinities with the target protein having ΔGb = -8.88 and -7.52; inhibition constant (ki) = 3.08 nM and 30.9 nM respectively.

Neuroprotective activity of natural products isolated from Senecio graciliflorus DC against corticosterone-induced impairment in SH-SY5Y cells.

Senecio graciliflorus DC root extract was studied for secondary metabolite composition following the bioactivity-guided isolation technique. The ethyl acetate extract of Senecio graciliflorus root yielded nine chemical constituents: 3,4-di-tert-butyl toluene, stigmasterol, ß-sitosterol, 2ß-(angeloyloxy)furanoeremophilane, gallic acid, 2ß-{[(Z)-2-hydroxymethylbut-2-enoyl]oxy}furanoeremophilane, 1-hydroxypentan-2-yl-4-methylbenzoate, sarcinic acid, and sitosterol 3-O-ß-D-glucopyranoside. The structures of the chemical constituents were elucidated on the basis of spectral data analysis in the light of literature. All the compounds are being reported for the first time from this plant. The isolated constituents were screened for neuroprotective effects against corticosterone-induced impairment in neuroblastoma cell lines (SH-SY5S cells). The viability of SH-SY5S cells was determined using MTT assay. Among various isolated compounds, three natural products (sarcinic acid, gallic acid, and ß-sitosterol) displayed robust neurotropic activity. The compounds increased neuronal cell survival in differentiated neuroblastoma cells (SH-SY5Y) from high-dose corticosterone (400 µM)-induced cell death. All the three constituents showed maximum AKT/ERK pathway activation at 20 µM concentration. The studies are aimed to explore small molecules for treating neurodegeneration underlying various neurological disorders to restore neuronal cell plasticity.

Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents.

Diosgenin, a promising anticancer steroidal sapogenin, was isolated from Dioscorea deltoidea. Keeping its stereochemistry rich architecture intact, a scheme for the synthesis of novel diosgenin analogues was designed using Cu (I)-catalysed alkyne-azide cycloaddition in order to study their structure-activity relationship. Both diosgenin and its analogues exhibited interesting anti-proliferative effect against four human cancer cell lines viz. HBL-100 (breast), A549 (lung), HT-29 (colon) and HCT-116 (colon) using [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide] (MTT) assay. Among the synthesized analogues, Dgn-1 bearing a simple phenyl R moiety attached via triazole to the parent molecule was identified as the most potent analogue against A549 cancer cell line having IC50 of 5.54µM, better than the positive control (BEZ-235). Dgn-2 and Dgn-5 bearing o-nitrophenyl and o-cyanophenyl R moieties respectively, displayed impressive anti-proliferative activity against all the tested human cancer cell lines with IC50 values ranging from 5.77 to 9.44µM. The structure-activity relationship (SAR) revealed that the analogues with simple phenyl R moiety or electron withdrawing ortho substituted R moieties seem to have beneficial impact on the anti-proliferative activity.

Design and Synthesis of Antitumor Heck-Coupled Sclareol Analogues: Modulation of BH3 Family Members by SS-12 in Autophagy and Apoptotic Cell Death.

Sclareol, a promising anticancer labdane diterpene, was isolated from Salvia sclarea. Keeping the basic stereochemistry-rich framework of the molecule intact, a method for the synthesis of novel sclareol analogues was designed using palladium(II)-catalyzed oxidative Heck coupling reaction in order to study their structure-activity relationship. Both sclareol and its derivatives showed an interesting cytotoxicity profile, with 15-(4-fluorophenyl)sclareol (SS-12) as the most potent analogue, having IC50 = 0.082 µM against PC-3 cells. It was found that SS-12 commonly interacts with Bcl-2 and Beclin 1 BH3 domain proteins and enhances autophagic flux by modulating autophagy-related proteins. Moreover, inhibition of autophagy by autophagy inhibitors protected against SS-12-induced apoptosis. Finally, SS-12 effectively suppressed tumor growth in vivo in Ehrlich's ascitic and solid Sarcoma-180 mouse models.