Unlocking the Drug Potential of the Bryostatin Family: Recent Advances in Product Synthesis and Biomedical Applications

Abstract

Bryostatins are a class of naturally occurring macrocyclic lactones with a unique fast developing portfolio of clinical applications, including treatment of AIDS, Alzheimer's disease, and cancer. This comprehensive account summarizes the recent progress (2014–present) in the development of bryostatins, including their total synthesis and biomedical applications. An emphasis is placed on the discussion of bryostatin 1, the most‐studied analogue to date. This review highlights the synthetic and biological challenges of bryostatins and provides an outlook on their future development.

Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer’s Disease

“…Bryostatins possess antitumor activity and immune modulatory properties, and also been demonstrated to be able to enhance memory and learning [ 56 ]. Bryostatin-1, a macrolide lactone with 11 chiral centers, is a potent modulator of PKC, a multifunctional protein responsible for cell differentiation and signal transduction [ 57 ]. Of the family of PKC isozymes, it was found that PKCε was involved in learning and memory and was deficient in fresh frozen hippocampal brain samples from AD patients [ 55 ].…”

“…Bryostatin-1 activates PKCε by binding to the N -terminus C1 domains of PKC causing autophosphorylation, protein translocation, and ubiquitination of PKC, thereby downregulating the protein. The normal levels are restored by de novo synthesis of the protein [ 52 , 57 ]. The activation of PKCε causes degradation of Aβ, activation of α-secretase, generating the synaptogenic non-toxic soluble amyloid-β protein precursor α and reduction of GSK3-β activity, thus decreasing hyperphosphorylation of tau [ 55 ].…”

The Phylum Bryozoa: From Biology to Biomedical Potential

“…Bryozoan metabolites exhibiting in vitro anticancer properties were comprehensively and recently reviewed by Pejin et al [111], Wu et al [11], Tian et al [10], and Figuerola and Avila [12]. Bioactive bryozoan metabolites were also discussed by Skropeta and Wei [112] reviewing advances in deep-sea natural product research, as well as by Hegazy et al [113] reviewing biomedical leads from Red Sea marine invertebrates.…”

“…To overcome these hurdles, several approaches can be actuated, including marine invertebrate aquaculture, synthesis, partial synthesis, and symbiont culture, all of which strongly depend on the biology of the producing organisms and on the true origin of the bioactive compounds. Tian et al [10] and Wu et al [11] already comprehensively reviewed this topic. Below, we outline our perspectives on these crucial aspects that are hoped to enable bryozoan metabolites to be used in human medicines.…”

“…It outlines aspects about general biology and evolutionary history of bryozoans and illustrates how bryozoans with the help of their metabolites shape chemoecologial interactions in the wild (Section 2). As anticancer activities of bryozoan metabolites have been recently reviewed by several authors [10][11][12], this review summarizes how selected compounds from bryozoans may complement existing treatments while outlining the shortcomings of current cancer treatments, as well as the problems and mechanisms associated with metastatic growth (Sections 3 and 4). Compounds holding promise to treat Alzheimer's disease, post-stroke damage, and Parkinson's disease are treated in Section 5.…”