Riviciclib

Rohitukine is a chromone alkaloid and precursor of potent anticancer drugs flavopiridol, P-276-00, and 2,6-dichloro-styryl derivative (11d) (IIIM-290). The metabolite is reported to possess anticancer, anti-inflammatory, antiadipogenic, immunomodulatory, gastroprotective, anti-implantation, antidyslipidemic, anti-arthritic, and anti-fertility properties. However, the physiological role of rohitukine in plant system is yet to be explored. Here, we studied the effect of rohitukine isolated from Dysoxylum gotadhora on Arabidopsis thaliana. The A. thaliana plants grown on a medium fortified with different rohitukine concentrations showed a significant effect on the growth and development. The root growth of A. thaliana seedlings showed considerable inhibition when grown on medium containing 1.0 mM of rohitukine. Transcriptomic analysis indicated the expression of 895 and 932 genes in control and treated samples respectively at a cut-off of FPKM ≥ 1 and P-value < 0.05. Gene ontology (GO) analysis revealed the upregulation of genes related to photosynthesis, membrane transport, antioxidation, xenobiotic degradation, and some transcription factors (TFs) in response to rohitukine. Conversely, rohitukine downregulated several genes including RNA helicases and those involved in nitrogen compound metabolism. The RNA-seq result was also validated by real-time qRT-PCR analysis. In light of these results, we discuss (i) likely ecological importance of rohitukine in parent plant as well as (ii) comparison between responses to rohitukine treatment in plants and mammals.

Dysoxylum binectariferum is an important medicinal plant distributed in the Western Ghats of India. The species has gained international importance for its anticancer component, rohitukine, a chromone alkaloid. Flavopiridol, P-276-00 and IIIM-290 are the derivatives of rohitukine in clinical trials against a wide range of cancers. Flavopiridol was recently approved as an orphan drug for chronic lymphocytic leukemia treatment. In this study, we report the isolation and characterization of rohitukine from the bark of D. binectariferum. Further, rohitukine was estimated across the Western-Ghats and the North-East regions of India. Additionally, D. binectariferum is also reported (∼45 compounds) to produce many natural derivatives of rohitukine and terpenoids, which were investigated in-silico to reveal promising CDK inhibitors. The metabolite fingerprinting of tissues of D. binectariferum was studied using HPTLC and FTIR. The distribution of major chromone alkaloid rohitukine was estimated by HPLC. Further, the pharmacological potential of D. binectariferum compounds was evaluated in-silico by discovering the potential protein targets, molecular docking, ADMET analysis and MD simulation. The isolation of rohitukine has yielded 0.6% from the bark of D. binectariferum. A higher percent of rohitukine was found in the Jog populations (0.58% & 1.28%: leaf & bark), whereas least was observed in the Phasighat population (∼0.06%: both leaf & bark). Across the geographic regions, a higher percent of rohitukine was found in the Central-southern Western Ghats, whereas lower in the northern parts of the Western Ghats and Northeast regions. The leaves produce a considerably higher percent of rohitukine and could be used as a sustainable source of rohitukine. The rohitukine analogues, along with other chromone alkaloids of D. binecatariferum were found to be more interactive with the "kinases" family of proteins, majorly "Serine/threonine-protein kinase PFTAIRE-2" (CDK15) with high confidence level (0.94-0.98). The molecular docking of these chromone alkaloids found a strong binding energy with six CDKs (-3.1 to -10.6 kcal/mol) along with a promising ADMET profile. In addition, molecular dynamic simulation found that the rohitukine complexes are virtually constant with CDK-1, 2, 9 and 15, which is substantiated with MM-PBSA free energy calculations. The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs.