Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors.

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.

An Etiological Investigation of Paraneoplastic Cerebellar Degeneration in Ovarian Cancer Patients: A Systematic Review.

Paraneoplastic syndromes (PNS) are uncommon, distinct clinical complications of a primary tumor. Paraneoplastic cerebellar degeneration (PCD) is a PNS that is described as an autoimmune response targeting Purkinje cells in the cerebellum. Ovarian cancer (OC) is one of the most prevalent causes of cancer-related deaths in women. Anti-Yo is the most common onconeural antibody produced in the PCD immune response and is most typically found in ovarian and breast cancer patients. While the current literature highlights the predisposing genetic factors, diagnostic workflows, and treatment options, the pathophysiology of PCD, among other considerations, remains largely unestablished. This review aimed to systematically observe procedural solutions to facilitate an early diagnosis and improve the prognosis of patients with OC-associated PCD. To that end, we examined literature published from 01/01/2015-11/10/2022 indexed in PubMed by using the keywords "paraneoplastic, cerebellar degeneration" combined with "ovarian cancer." Inclusion criteria were met if PCD and OC diagnoses were made and if studies provided adequate patient information. After screening and assessing records for eligibility using the inclusion and exclusion criteria, 18 articles involving 102 patients were included. The typical patient observed in this sample was diagnosed with International Federation of Gynecology and Obstetrics (FIGO) Stage III, high-grade serous carcinoma. The diagnostic workup typically included a clinical evaluation for dysarthria (50%), ataxia (60%), and gait abnormalities (50%), along with multiple imaging modalities and serological findings (90%). Genetic screening for human leukocyte antigen (HLA) haplotype susceptibility for PCD and immune tolerance modulators regulation may also be recommended prior to starting treatment. Findings support the use of corticosteroids (35%) and intravenous immunoglobulin (IVIg) (40%) as viable treatment options for managing PCD in conjunction with systemic therapy for the primary malignancy. A diagnosis of PCD should be considered if a patient has had a malignancy in the past five years with the presence of explicit cerebellar symptoms. This clinical diagnosis can be further supplemented by serologic and radiologic findings. Recognizing PCD symptoms and scheduling genetic and proteomic testing may help with early diagnosis and better prognosis.