Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of 11d for advancement in clinical studies.
Chromone alkaloids and flavoalkaloids are an important group of natural products possessing promising medicinal properties. A chromone alkaloid rohitukine is a major bioactive chemical constituent of plant Dysoxylum binectariferum (Meliaceae) Hook. which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd. used for treatment of rheumatoid arthritis. This chromone alkaloid led to discovery of two synthetic flavoalkaloids: flavopiridol (Sanofi) and P-276-00 (Piramal) which have reached to advanced stages of clinical development for cancer treatment. Flavopiridol (Alvocidib; L868275; HMR-1275; NSC 649890 of Sanofi-Aventis + NCI) is approved as an orphan drug for treatment of chronic lymphocytic leukemia and is currently undergoing phase II studies as monotherapy and also as in combination regimes with traditional chemotherapy agents. P-276-00 (12) is currently in phase II clinical studies for advanced refractory neoplasms and multiple myeloma. Extensive amount of medicinal chemistry efforts have been reported on these flavoalkaloids. Flavopiridol demonstrated potent and specific in vitro inhibition of variety of cyclindependent kinases with clear block in cell cycle progression at the G1/S and G2/M phases. Preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The co-crystallised structure of deschloro-flavopiridol with CDK-2 is available and key interactions in the ATP binding site have been reported. Flavopiridol has also been studied for the treatment of arthritis and atherosclerotic plaque formation. The present review comprises discovery, medicinal chemistry, pharmacology and preclinical/clinical development of flavoalkaloids as CDK inhibitors.
Rapid assessment of radiation signatures in non-invasive biofluids may aid in assigning proper medical treatments for acute radiation syndrome (ARS) and delegating limited resources after a nuclear disaster. Metabolomic platforms allow for rapid screening of biofluid signatures and show promise in differentiating radiation quality and time postexposure. Here, we use global metabolomics to differentiate temporal effects (1-60 d) found in nonhuman primate (NHP) urine and serum small molecule signatures after a 4 Gy total body irradiation. Random Forests analysis differentially classifies biofluid signatures according to days post 4 Gy exposure. Eight compounds involved in protein metabolism, fatty acid β oxidation, DNA base deamination, and general energy metabolism were identified in each urine and serum sample and validated through tandem MS. The greatest perturbations were seen at 1 d in urine and 1-21 d in serum. Furthermore, we developed a targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM) method to quantify a six compound panel (hypoxanthine, carnitine, acetylcarnitine, proline, taurine, and citrulline) identified in a previous training cohort at 7 d after a 4 Gy exposure. The highest sensitivity and specificity for classifying exposure at 7 d after a 4 Gy exposure included carnitine and acetylcarnitine in urine and taurine, carnitine, and hypoxanthine in serum. Receiver operator characteristic (ROC) curve analysis using *
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.