Total synthesis of debromoaplysiatoxin and aplysiatoxin

Park, Pyeong Uk; Broka, Chris A.; Johnson, Bruce; Kishi, Yoshito

doi:10.1021/ja00254a062

Cited by 75 publications

(30 citation statements)

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“…1. The synthetic route was virtually identical to the one utilized for the total synthesis of DAT and aplysiatoxin (20), except that properly protected diastereomeric or enantiomeric 3,4-dihydroxyvaleryl chloride was used to introduce the C27-C31 moiety of each of the DAT analogs.…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis was carried out as summarized in Fig. 1, using the synthetic intermediate employed in the total synthesis of aplysiatoxins (20) as starting material. One of the key steps in this synthesis was the base-induced spiroketal formation (in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Structure-activity studies in the simple diglyceride series have been disappointing thus far in the search for a structural model, as virtually any modification of the parent structures leads to molecules with trivial activities (9). The prospect of undertaking structure-activity relationship studies on the more potent tumor promoters was made possible by the recent total synthesis of DAT' (20). The potency.…”

Section: Discussionmentioning

confidence: 99%

“…Critical to these studies is the ability to synthetically manipulate DAT to test the current hypotheses. The synthetic work is based on the total synthesis ofaplysiatoxins (20), which enables crucial structural modifications to be performed. With this in mind, all the stereoisomers of DAT and 3-deoxy-DAT with respect to the C29 and C30 positions were synthesized, and assayed as PKC activators.…”

mentioning

confidence: 99%

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Structural basis of protein kinase C activation by tumor promoters.

Nakamura

Kishi

Pajares

et al. 1989

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

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Protein kinase C (PKC) is an important enzyme that helps govern cell metabolism and growth. The enzyme is physiologically activated when an (S)-diglyceride binds to its own regulatory domain. The saturable binding site of the regulatory domain can also be bound by any of a group of structurally diverse tumor promoters, including debromoaplysiatoxins (DATs), phorbol esters, ingenols, teleocidins, and bryostatins. The question of how the same binding site can be the target of these structurally diverse molecules is of considerable importance and is addressed in this article. The relatively rigid structure of DAT and the fact that it possesses a diglyceride moiety renders it an ideal starting template. Structure-activity studies with PKC reveal that the C29 but not the C30 stereocenter of DAT is critical for activity. Furthermore, 3-deoxy-DAT and DAT are equipotent as PKC activators, hence the C3 hydroxyl group of DAT is not critical for activity. Straightforward structural considerations show that the C30 hydroxyl group ofDAT matches the C3 hydroxyl group of diglyceride, the C29 stereocenter of DAT matches the C2 stereocenter of (S)-diglyceride, and the C1 ester moiety of DAT matches the C2 ester moiety of diglyceride. Based on these studies and on published structure-activity observations on other tumor promoters, a structural hypothesis is developed to account for the chemical mechanism of tumor promoter action. Experimentally testable predictions are made concerning the interactions with PKC of several classes of tumor PKC activators.A central question in the mechanism of protein kinase C (PKC) action is concerned with the nature of the activation process. This physiologically important enzyme is activated when a diglyceride binds to an effector site on its regulatory domain (1, 2). The diglyceride itself is produced as a consequence of the regulated hydrolysis of phosphatidylinositol phosphates by a specific phospholipase (3). The interaction of PKC with diglyceride is stoichiometric (4) and stereospecific, with the (S)-enantiomer being active (5, 6). The specificity of this process has been further probed with diglyceride analogs (7-9). These studies have shown an unusual degree of specificity directed toward the glycerol backbone and the hydrophilic moieties of the diglycerides. The strict specificity shown toward the diglycerides must be contrasted with the behavior of PKC toward the tumor promoters, including phorbol esters, ingenols, aplysiatoxins, and teleocidins (see Fig. 7). All these structurally diverse molecules share PKC as their common target and appear to function by binding to and activating the enzyme permanently, whereas the diglycerides bind and activate temporarily (10)(11)(12).Given that it is highly likely that the various tumor promoters and active diglycerides bind to the same site on the regulatory domain ofPKC, it must be possible to demonstrate structural commonalities in these various agents. Several models, generated by various computer-driven modeling protocols, have alread...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Structural basis of protein kinase C activation by tumor promoters.

Nakamura

Kishi

Pajares

et al. 1989

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

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“…Kishi and co-workers were first to achieve the complete synthesis of ATX, 101 and Yamaguchi and co-workers reported the production of an asymmetric form. [102][103][104] Moreover, Yamamura and co-workers synthesized the chemically stable 3-deoxy-debromo-ATX, 105,106 and an unique spiroketal construction with a Diels-Alder reaction was reported in the synthesis of 3-deoxy-20-O-Me-ATX by Ireland and co-workers.…”

Section: Attempts To Develop New Anticancer Drugs Based On the Skeletmentioning

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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