Study of potent CDK7 inhibitor secondary metabolites from Tecomella undulata.

Chemical investigation of the petroleum ether extract of heartwood of Tecomella undulata led to the isolation of tectonaquinone B (1), 2-methylquinizarin (2) along with tecomaquinone I (3), lapachol (4), 2-isopropenylnaphtho[2,3-b]-furan-4,9-quinone (5), dehydro-α-lapachone (6), α-lapachone (7), and ß-lapachone (8). This is the first report of isolation of tectonaquinone B and 2-methylquinizarin from this plant. The structures of compounds were elucidated by advanced spectroscopic methods. Molecular docking study for potential inhibitory action toward CDK7 (cyclin-dependent kinase 7) were performed, which proved that these compounds have high binding affinities with the receptor protein (CDK7). 2-Methylquinizarin exhibited best docking score (-7.70 kcal/mol) among all the tested compounds. The present study showed that 2-methylquinizarin may exhibit potent anticancer activity through inhibiting CDK7 via interaction with Met94.

Isolation and characterization of cyclotides from the leaves of Viola odorata L. using peptidomic and bioinformatic approach.

Cyclotides are true gene products characterized by the presence of six conserved cysteine residues and knotted arrangement of three disulfide bonds. These macrocyclic peptides show exceptional resistance to thermal, chemical and enzymatic degradation which is defined due to their three-dimensional folding. The current study describes an efficient strategy involving reduction, enzymatic digestion and mass spectroscopy sequencing for the identification of the precursor sequences and the cyclotide domains present in the leaf tissue of Viola odorata. We observed 122 partial peptide sequences containing 31 cyclotide domains along with 19 unique sequences consisting of putative novel cyclotides and acyclotides. Four precursor sequences consisting of putative new and already reported domains were further characterized for cyclotide domains, their structure and subfamilies. The sequences revealed the presence of classic knotted cyclotide folds with similar six characteristic loops but different amino acid residues. Molecular modeling indicated that the secondary structures present in the cyclotides are mainly α-helix and random coils. Variation in the sequences and conservation in cysteine residues in the cyclotides was revealed by protein diversity wheel. The significant information observed in the current study expands our knowledge about the structure and type of cyclic peptides in V. odorata leaves. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02763-2.

Natural Products in Mitigation of SARS CoV Infections.

Severe acute respiratory syndrome (SARS) is a critical respiratory disease caused by coronaviruses (CoV). The available antiviral agents or host-specific antiinflammatory therapies are the principal treatment modalities, with drug-repurposing as the most viable approach to timely tackle the CoV pandemic. Though these approaches are successful to some extent in reducing the mortality rate, however, it is too far to see a complete escape from the current SARS CoV-2 pandemic. Plants are the primary source of diet, dietary supplements, botanical drugs, and natural products (NPs). It has been well accepted and proved via several scientific studies that plant-based therapies play a vital role in managing such infections. The faulty immune system (compromised innate immunity or aberrant immune activation) determines the severity of the respiratory distress in CoV-2 infected patients. Natural products intervene at various stages of the virus replication cycle, including inhibition of virus entry into the host cells, inhibition of serine/ cysteine proteases, RNA-dependent RNA polymerase (RdRp) or helicase. Besides, several natural products or plant-based dietary supplements have a unique ability to strengthen the immune system or alleviate the hyper-inflammatory condition. Many plant-based formulations, dietary supplements, and NPs are being investigated in clinical trials in CoV-2 infected patients, and few have already shown positive results. The review has unearthed several NP leads for medicinal chemistry programs as well as some having direct opportunity of repurposing in SARS CoV infections.

Carbohydrate Modifications of Neoandrographolide for Improved Reactive Oxygen Species-Mediated Apoptosis through Mitochondrial Pathway in Colon Cancer.

Modifications at the carbohydrate moiety of neoandrographolide, isolated from the medicinal plant Andrographis paniculata, result in more potent and less toxic derivatives, namely, 4',6'-benzylidene neoandrographolide (2b) and 4'6'-p-methoxybenzylidene neoandrographolide (2c). These showed improved cytotoxicity against SW-620, PC-3, and A549 cancer cell lines. Nuclear morphology studies were conducted on compound 2b by 4',6-diamidino-2-phenylidole staining and detection of intracellular reactive oxygen species (ROS) accumulation. It showed an increase in the generation of cellular and mitochondrial ROS level. The probable relation of B-cell lymphoma-2 (Bcl-2, an apoptosis inhibitor) to B-cell lymphoma-2-associated X protein (Bax, an apoptosis promoter) ratio with caspase-3 (apoptosis coordination enzyme) in the colon cancer cell line SW-620 was investigated, and it was discovered that upon 2b treatment, the expression of caspase-3 Bax increased remarkably. However, in 2b-treated cells, the expression of Bcl-2 was downregulated as compared to untreated cells.