Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review.

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.

Isolation, analytical measurements, and cell line studies of the iron-bryostatin-1 complex.

Bryostatin-1 is a marine natural product that has demonstrated medicinal activity in pre-clinical and clinical trials for the treatment of cancer, Alzheimer's disease, effects of stroke, and HIV. In this study, iron-bryostatin-1 was obtained using a pharmaceutical aquaculture technique developed by our lab that cultivates marine bacteria for marine natural product extraction. Analytical measurements (1)H and (13)C NMR, mass spectrometry, and flame atomic absorption were utilized to confirm the presence of an iron-bryostatin-1 complex. The iron-bryostatin-1 complex produced was then tested against the National Cancer Institute's 60 cell line panel. Adding iron to bryostatin-1 lowered the anti-cancer efficacy of the compound.

Cytotoxic Bryostatin Derivatives from the South China Sea Bryozoan Bugula neritina.

Four new macrocyclic lactones, bryostatin 21 (1) and 9-O-methylbryostatins 4, 16, and 17 (2-4), together with three known related compounds, bryostatins 4, 16, and 17 (5-7), have been isolated from an extract of the South China Sea bryozoan Bugula neritina. The structures of all compounds were unambiguously elucidated using detailed spectroscopic analysis. Structurally, the presence of a single methyl group at C-18 in compound 1 has not been observed before for known bryostatins. The isolated macrolides exhibited inhibitory effects against a small panel of human cancer cell lines.

[Search for natural substances with therapeutic activity: George R. Pettit]. / Recherche de substances naturelles à activité thérapeutique (2) - George R. Pettit.

This series of brief reviews covers the "life and work" of famous and iconic researchers who discovered major therapeutics from natural products: their life history, the circumstances of their discoveries, the molecules and their molecular, cellular and physiological mechanisms of action, and their biomedical applications. Dedicated to George R. Pettit, the second article reviews the life of the famous researcher, his worldwide exploration of natural products, especially of marine origin, in search of promising anticancer leads, his discovery and structural elucidation of very potent drug candidates, their synthesis and the launch of some of them on the pharmaceutical market. An extraordinary scientific career which lead George R. Pettit from exploration of Nature to state-of-the-art analytical and synthetic chemistry and from clinical trials to therapeutic successes.

Identification and biological activities of bryostatins from Japanese bryozoan.

Six bryostatins were isolated from Japanese bryozoan by evaluating their binding to the C1B domain of protein kinase Cδ (PKCδ). Structure-activity studies of bryostatins 4, 10, and 14 suggested that the ester group at C20 was not necessary for binding to and activating PKCδ. These bryostatins showed significant anti-tumor-promoting activity in induction tests with the Epstein-Barr virus early antigen.

[Advance of several types of important marine antitumor drugs].

Marine antitumor drugs have been the research focus in the world. Recently, advancement has been made in the investigation of six types of compounds including bryostatin-1, ecteinascidin-743, dolastatin, didemnin B, psammaplin and halichondrin B. In this review, we summarized the recent research progress of the above mentioned marine antitumor drugs and their derivatives. Also, the development tendency of marine antitumor drugs was discussed.