Naturally occurring heterocyclic anticancer compounds

Naturally occurring heterocyclic scaffolds are key ingredients for the development of various therapeutics employed for biomedical applications. Heterocyclic pharmacophores are widely disseminated and have been befallen in almost all categories of drugs for the alleviation of myriad ailments including diabetes, neurodegenerative, psychiatric, microbial infections, disastrous cancers etc. Countless fused heterocyclic anticancerous templates are reported to display antimetabolite, antioxidant, antiproliferative, cytostatic etc. pharmacological actions via targeting different signaling pathways (cell cycle, PI-3kinase/Akt, p53, caspase extrinsic pathway etc.), overexpressive receptors (EGRF, HER2, EGF, VEGF etc.) and physiological enzymes (topoisomerase I and II, cyclin dependent kinase etc.). A compiled description on various natural sources (plants, microbes, marine) containing anticancer agents comprising heterocyclic ring specified with presence of nitrogen (vincristine, vinblastine, indole-3-carbinol, meridianins, piperine, lamellarins etc.), oxygen (paclitaxel, halichondrin B, quercetin, myricetin, kaempferol etc.) and sulphur atoms (brugine, fucoidan, carrageenan etc.) are displayed here along with their molecular level cytotoxic action and therapeutic applications.

Drug Leads Derived from Japanese Marine Organisms

: Many natural products with extraordinary chemical structures and brilliant biological activities have been obtained from marine organisms. We have investigated such fascinating bioactive molecules, exemplified by the potent marine toxin palytoxin and the antitumor molecule halichondrin B, which has been developed as the anticancer drug Halaven®, to explore novel frontiers in organic chemistry and bioscience. Working within the traditional discipline, we have sought to acquire a deeper understanding of biological phenomena. We introduce here our major work along with up-todate topics. We isolated yoshinone A from marine cyanobacteria and completed a gram-scale synthesis. Yoshinone A is a novel polyketide that inhibited the differentiation of 3T3-L1 cells into adipocytes without significant cytotoxicity. The detailed mechanisms of action will be elucidated via further experiments in vitro and in vivo. In this study, we explore the true producers of okadaic acid and halichondrin B by immunostaining of Halichondria okadai with an antibody that was prepared using these natural products as an antigen. We will analyze isolated symbionts and reveal biosynthetic pathways.

Eribulin in the Management of Advanced Breast Cancer: Implications of Current Research Findings

The search for cytotoxic agents from marine natural products ultimately led to the production of eribulin, which is a synthetic macrocyclic ketone analog of halichondrin B. Eribulin binds to tubulin to induce mitotic arrest and gained approval in Japan in May 2010; it was approved by the US Food and Drug Administration in November 2010 and the European Medicines Agency in March 2011 and was reimbursed by the Taiwan National Health Insurance in December 2014 for patients with metastatic breast cancer who had received at least one anthracycline and one taxane. The recommended regimen for eribulin mesylate comprises intravenous administration of 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin) over two to five minutes on days 1 and 8 of a three-week cycle. Since 2011, various clinical investigations of eribulin monotherapy with dose or schedule modifications, combined use with other antineoplastic therapeutics, or head-to-head comparisons with specific agents have been performed in the management of advanced breast cancer. Ethnic-specific data from Japan and Korea indicate higher rates (>85%) of grade 3 or 4 neutropenia. Some anecdotal evidence suggests that eribulin can shrink brain and retinal metastases, which warrants further detailed studies. In this review, current observations of the effects of eribulin monotherapy are summarized and eribulin-backbone combination (bio-) chemotherapy is investigated.

Identification of potential molecular biomarkers for response of soft tissue sarcoma to eribulin: Translational results of EORTC trial 62052.

10573 Background: The phase II study EORTC 62052 demonstrated potential antitumor activity of eribulin, a tubulin-interacting cytotoxic agent, which is a synthetic analogue of the natural compound halichondrin B, in patients with various subtypes of metastatic soft tissue sarcoma (STS) including leiomyo- (LMS) and adipocytic (ADI) sarcomas, but not synovial sarcomas (SYN) and other sarcoma histotypes (OTH) (Schöffski P et al. Lancet Oncol. 2011;12:1045). In addition to histotypes, we aimed to identify potential biomarkers responsible for eribulin sensitivity or resistance to eribulin using gene expression and miRNA profiling. Methods: From 68 consenting patients archived tumor tissue was collected, including 22 LMS, 15 ADI, 10 SYN and 21 OTH sarcoma histotypes. Total RNA was isolated from 65 samples and analyzed using GeneChip Human Exon ST Array (for mRNA expression) and Taqman Low Density Array (for miRNA). Progression free survival (PFS) at week 12 (RECIST 1.0) was the primary endpoint of the clinical trial and used for correlative studies. Eighteen out of 56 (32.1%) evaluable patients in this analyzed subset had non progressive disease at week 12 (“responders”). Results: Overall expression of 62 transcripts including ALS2CR11 (uncorrected p<0.001) and 26 miRNAs (p<0.05) differed significantly between non-responders and responders. Additional transcripts and miRNAs were identified when considering the different histological groups (Table). Conclusions: The level of (mi)RNA expression in soft tissue sarcoma samples may predict response of soft tissue sarcoma to eribulin. Further validation studies are required. [Table: see text]