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Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A ( 1 ), diportharine A ( 2 ) and xylarolide B ( 3 ) along with one known compound xylarolide ( 4 ). The structures of all the compounds ( 1 – 4 ) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 1 – 3 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A ( 1 ) and xylarolide ( 4 ) displayed significant growth inhibition of MIAPaCa-2 with an IC 50 of 20 and 32  µ M respectively and against PC-3 with an IC 50 of 14 and 18  µ M respectively. Moreover, compound 1 displayed significant DPPH scavenging activity with EC 50 of 10.3  µ M using ascorbic acid as a positive control. [ABSTRACT FROM AUTHOR]

Rohitukine is a chromone alkaloid isolated from an Indian medicinal plant Dysoxylum binectariferum . This natural product has led to the discovery of two clinical candidates (flavopiridol and P276-00) for the treatment of cancer. Herein, for the first time we report an efficient protocol for isolation and purification of this precious natural product in a bulk-quantity from leaves (a renewable source) of D. binectariferum (>98% purity) without use of chromatography or any acid–base treatment. Despite of the fact that this scaffold has reached up to clinical stage, particularly for leukemia; however the antileukemic activity of a parent natural product has never been investigated. Furthermore, rohitukine has never been studied for cyclin-dependent kinase (Cdk) inhibition, kinase profiling and for its experimental physicochemical properties. Thus, herein, we report in vitro cytotoxicity of rohitukine in a panel of 20 cancer cell lines (including leukemia, pancreatic, prostate, breast and CNS) and 2 normal cell lines; kinase profiling, Cdk2/9 inhibition, and physicochemical properties (solubility and stability in biological medias, p K a , Log P , Log D ). In cytotoxicity screening, rohitukine displayed promising activity in HL-60 and Molt-4 (leukemia) cell lines with GI 50 of 10 and 12 μM, respectively. It showed inhibition of Cdk2/A and Cdk9/T1 with IC 50 values of 7.3 and 0.3 μM, respectively. The key interactions of rohitukine with Cdk9 was also studied by molecular modeling. Rohitukine was found to be highly water soluble ( S water = 10.3 mg/mL) and its Log P value was −0.55. The ionization constant of rohitukine was found to be 5.83. Rohitukine was stable in various biological media’s including rat plasma. The data presented herein will help in designing better anticancer agents in future. [ABSTRACT FROM AUTHOR]

Embelin ( 1 ), a benzoquinone isolated from Embelia ribes is known to possess variety of biological activities. Despite of several promising biological activities, preclinical efforts on embelin were hampered because of its poor aqueous solubility. In order to address the solubility issue, herein, we have synthesized a series of Mannich products of embelin by treating it with various secondary amines. The synthesized compounds were screened for antiproliferative and antimicrobial activities. In cytotoxicity screening, the benzyl-piperidine linked derivative 8m was found to possess better antiproliferative activity compared to parent natural product embelin against a panel of cell lines including HCT-116, MCF-7, MIAPaCa-2 and PC-3 with IC 50 values of 30, 41, 34 and 36 μM, respectively. The mechanistic study of compound 8m revealed that it exhibits cytotoxicity via induction of apoptosis and mitochondrial membrane potential loss. Further, the compounds were tested for antimicrobial activity where dimethylamino- 8a and piperidine linked derivative 8b displayed antibacterial activity against Staphylococcus aureus with MIC values of 8 and 16 μg/mL, respectively. Mannich derivatives did now show improved aqueous solubility, however their hydrochloride salts 8a ·HCl, 8b ·HCl and 8m ·HCl showed significantly improved aqueous solubility without affecting biological activities of parent Mannich derivatives. [ABSTRACT FROM AUTHOR]

A target synthesis of a library of symmetric aromatic diselenides was attempted with the aim of generating anticancer lead compounds. Out of thirteen screened molecules ( 1 – 13 ) against a panel of human cancer cell lines, compound 8 exhibited highest cell growth inhibition in Human leukemia HL-60 cells with IC 50 value of 8 μM. Compound 8 had a good pro-apoptotic potential as evidenced from several apoptotic protocols like DNA cell cycle analysis and monitoring of apoptotic bodies formation using phase contrast and nuclear microscopy with Hoechst 33,258. Also, 8 significantly inhibits S phase of the cell cycle and eventually trigger apoptosis in HL-60 cells through mitochondrial dependent pathway substantiated by the loss of mitochondrial potential. A theoretical investigation of DNA binding ability of 8 showed that it selectively bind to minor groove of DNA, where it is stabilized by hydrogen bonding and hydrophobic interactions. [ABSTRACT FROM AUTHOR]