Convergent Assembly of Highly Potent Analogues of Bryostatin 1 via Pyran Annulation: Bryostatin Look-Alikes That Mimic Phorbol Ester Function

Keck, Gary E.; Kraft, Matthew B.; Truong, Anh P.; Li, Wei; Sanchez, Carina; Kedei, Noémi; Lewin, Nancy E.; Blumberg, Peter M.

doi:10.1021/ja8022169

Cited by 91 publications

(86 citation statements)

References 19 publications

(16 reference statements)

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“…2011;11(11): 1370- 92 The final version of record is available at http://www.eurekaselect.com/88010/article DOI: 10.2174/156802611795589584 11 was proven correct by the corresponding pivaloyloxy (analogue 17) and methylene (analogue 18) derivatives, which showed better binding affinities (Ki of 6.6 and 5.3 nM, respectively) compared to compound 14. Furthermore, the Blumberg group showed that the removal of the methyl and hydroxyl groups in ring A of bryostatin 1 gave compounds that retained excellent binding to PKCα (0.7-3.0 nM, compounds 21-24) but that evoked phorbol-like tumor promoting responses [50,51]. Alternatively, compound 11, which has the same C7-C9 substituents as bryostatin 1 and lacks only the C30 methoxy carbonyl group, showed a Ki value of 0.52 nM for PKCα but is also a functional antagonist of PMA (8) [52].…”

Section: Structure-activity Studiesmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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Protein kinase C (PKC) comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. PKC isoforms respond to Gprotein coupled receptor-and receptor tyrosine kinase-signaling via binding the second messenger diacylglycerol with C1 domains. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders.Drug discovery concerning C1 domains has exploited natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

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Section: Structure-activity Studiesmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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“…4). [53][54][55] They found that 3 exhibited greater affinity for PKCa than did bryo-1. They also tested the function of 3 using U937 leukemia cells.…”

Section: Challenges To the Development Of Anticancer Drugs Kmentioning

confidence: 99%

Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ

Irie

Yanagita

Nakagawa

2010

Medicinal Research Reviews

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Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo-1) is a unique PKC activator with little tumor-promoting activities. Bryo-1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo-1-related compounds have been developed, the identification of synthetically more accessible compounds with bryo-1-like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo-1's unique mechanism of activating PKCδ that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog-1) of the tumor-promoting aplysiatoxin showed PKCδ-activating behavior similar to bryo-1. Aplog-1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor-promoting activity in vitro was very weak, and its cell growth-inhibitory activities were comparable to those of bryo-1. These data suggest that aplog-1 could become another therapeutic lead for cancer.

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“…This compound possesses excellent affinity for PKC (K i ¼ 3 nM), is orders of magnitude more potent than bryostatin against several human cancer cell lines, and can be synthesized in a step-economical fashion (29 total steps) scalable to meet clinical demand. Recent work by Keck and coworkers has provided further examples of the effectiveness of this design strategy (55)(56)(57)(58).…”

mentioning

confidence: 99%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

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Convergent Assembly of Highly Potent Analogues of Bryostatin 1 via Pyran Annulation: Bryostatin Look-Alikes That Mimic Phorbol Ester Function

Cited by 91 publications

References 19 publications

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

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