Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula
neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are
one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural
bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among
medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well
established, with the identification of key pharmacophoric features important for PKC modulation. The
low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with
simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a
macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate
the PKCα activity; however, the cyclic framework appears to be essential for the desired level of
potency. Another simplified analog 17 (“picolog”) exhibited potent and in-vivo efficacy against lymphoma.
Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and
displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease.
Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal
effect as a single agent, however, provided encouraging results in combination with other
chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with
paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X
syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV
infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to
emerge as treatment for cancer along with many other diseases.
Keywords: Bryostatins, Bryostatin-1, Protein kinase C, Clinical trials, Cancer, Alzheimer's disease.
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