Bromotyrosine-derived secondary metabolites from marine sponges of the order Verongida provide unique diversity in chemical structure and a wide range of biological activities. With a decline in the number of novel antibiotic scaffolds which are emerging and the on-going search for more effective antibacterial and anticancer drugs, these brominated metabolites are attractive candidates for further total synthesis and biological evaluation. An Efficient total synthesis of bromotyrosine alkaloids purpurealdin E (92), aplyzanzine A (122), suberedamine A (123) and B (124), iso-Anomoian A (121a) and aplysamine-2 (104) were achieved through the carbodiimide coupling of appropriate tyrosine/tyramine units in excellent yields. Their structures have been confirmed through direct comparison with spectroscopic data of isolated natural products. The key step was the one-pot Bocdeprotection, dimethylation and hydrolysis of desired intermediate, which was achieved in 88% yield. A new synthetic route was developed for the preparation of diverse analogues for biological assessment. This route utilized cheap and commercially available starting materials, and allowed access to various analogues inaccessible via currently reported methods. By utilising this route, the total syntheses of 5- bromoverongamine (207), 20-N-methylpu rpuramine E (208) , psammaplin A (150), psammaplin C (156), spermatinamine (50) and tokaradine A (209) were successfully carried out and are reported herein. These new syntheses of spermatinamine and psammaplin A are more efficient than previously reported sequences. In addition, we explored a method for the selective removal of benzyl protecting groups in the presence of both oxime and disulphide moieties. Aplyzanzine A (122) was found to be the most active product against a Grampositive bacterial and fungal screen demonstrating MIC values 2-4 times lower than the other compounds. All compounds, except purpurealdin E and psammaplin C, exhibit modest inhibition against M. bovis BCG and M. tuberculosis H37Rv. 20-N-methylpurpuramine-E (208) was most active with an MIC (5 μg/mL) towards M. bovis BCG. iso-Anomoian A (1 21a) and suberedamine B (124) showed antitumor activity in the NCI-DTP60 cell line screen at single micromolar concentrations, with iso-anomoian A (121 a) inhibiting 53 cell lines. These molecules present novel scaffolds for further optimization.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:592881 |
| Date | January 2014 |
| Creators | Kottakota, Suresh Kumar |
| Publisher | University of Sunderland |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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