Semisynthesis and biological evaluation of a cotylenin A mimic derived from fusicoccin A

Inoue, Takatsugu; Higuchi, Yusuke; Yoneyama, Toru; Lin, Bangzhong; Nunomura, Kazuto; Honma, Yoshio; Kato, Nobuo

doi:10.1016/j.bmcl.2018.01.030

Cited by 21 publications

(14 citation statements)

References 27 publications

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“…A recent study showed that replacing the acetyl with an acetamide (FC-NAc) improves the affinity to 14-3-3 with various partners . The 12-position is hydroxylated in the natural compounds, but this position is not hydroxylated in the semisynthetic derivatives DP-005 and ISIR-005, , and a bulky group was introduced for FC-THF . For FC-A-aglycon (FC-A-ag) and FC-J-aglycon (FC-J-ag), the sugar moiety was removed.…”

Section: Resultsmentioning

confidence: 99%

Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products

et al. 2020

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Natural compounds are an important class of potent drug molecules including some retrospectively found to act as stabilizers of protein–protein interactions (PPIs). However, the design of synthetic PPI stabilizers remains an understudied approach. To date, there are limited examples where cooperativity has been utilized to guide the optimization of a PPI stabilizer. The 14-3-3 scaffold proteins provide an excellent platform to explore PPI stabilization because these proteins mediate several hundred PPIs, and a class of natural compounds, the fusicoccanes, are known to stabilize a subset of 14-3-3 protein interactions. 14-3-3 has been reported to negatively regulate the p65 subunit of the NF-κB transcription factor, which qualifies this protein complex as a potential target for drug discovery to control cell proliferation. Here, we report the high-resolution crystal structures of two 14-3-3 binding motifs of p65 in complex with 14-3-3. A semisynthetic natural product derivative, DP-005, binds to an interface pocket of the p65/14-3-3 complex and concomitantly stabilizes it. Cooperativity analyses of this interaction, and other disease relevant 14-3-3-PPIs, demonstrated selectivity of DP-005 for the p65/14-3-3 complex. The adaptation of a cooperative binding model provided a general approach to characterize stabilization and to assay for selectivity of PPI stabilizers.

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Section: Resultsmentioning

confidence: 99%

Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products

et al. 2020

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“…Compounds 3 and 4 were readily prepared by converting the 6'-hydroxylg roup to an azido group startinge ither from compound 7 [25] or FC-J, respectively.B riefly,a fter removing the acetonide group of 7,t he 6'-hydroxyl group in 8 was tosylated to give 9 in 57 %y ield. Direct conversion of the tosyl group by using sodium azide was attempted, but difficulties during the purification prompted us to conducta na cetylation and subsequent substitution to give 10,w hichw as further hydrolyzed and reduced to 3 (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 3 and 4 were readily prepared by converting the 6′‐hydroxyl group to an azido group starting either from compound 7 or FC‐J, respectively. Briefly, after removing the acetonide group of 7 , the 6′‐hydroxyl group in 8 was tosylated to give 9 in 57 % yield.…”

Section: Resultsmentioning

confidence: 99%

Structural Effects of Fusicoccin upon Upregulation of 14‐3‐3‐Phospholigand Interaction and Cytotoxic Activity

Ohkanda

Kusumoto

Punzalan

et al. 2018

Chemistry A European J

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Fusicoccins (FCs) exhibit variousc ellular activities in mammalian cells, but detailso ft he mechanism of action are not fully understood. In this study,w esynthesized two pairs of model derivatives of FCs differing only in the presence and absence of a1 2-hydroxyl group and evaluated their binding to a1 4-3-3 protein together with various mode 1a nd mode 3p hosphopeptide ligands. Our results demonstrate that the 12-hydroxyl group hampersb inding to 14-3-3 with mode 1p hospholigands,p resumably due to steric repulsion with the i+ +2r esidue. Furthermore, cellbased evaluations showedt hat only non-substituted FCs exhibit significant cytotoxicity and all 12-hydroxyl derivatives were inactive, demonstrating ac lear correlation with their ability to form ternary complexes with 14-3-3 and am ode 1 ligand.T hese results suggest that binding to 14-3-3 and a partner protein(s) possessing am ode 1s equence plays a role in the mechanism of action of 12-non-substituted FCs.[a] Prof.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/chem.201804428:Experimental details for synthesis, in vitro evaluation,and cell-based experiments.

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“…As fusicoccin A and cotylenin A can play different roles in human cancers, hydroxylation of C12 might be considered as an adequate factor of structural specificity [ 19 ]. Another significant example that indicates the activity of CN-A in human cancers was given by the group of Kato, who suggested that ISIR-050 (designed as a CN-A mimic) and CN-A induce the same pharmacological response to IFNα-treated cancer cells [ 44 ].…”

Section: Stabilizers Of 14-3-3 Ppismentioning

confidence: 99%

14-3-3: A Case Study in PPI Modulation

2018

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In recent years, targeting the complex network of protein–protein interactions (PPIs) has been identified as a promising drug-discovery approach to develop new therapeutic strategies. 14-3-3 is a family of eukaryotic conserved regulatory proteins which are of high interest as potential targets for pharmacological intervention in human diseases, such as cancer and neurodegenerative and metabolic disorders. This viewpoint is built on the “hub” nature of the 14-3-3 proteins, binding to several hundred identified partners, consequently implicating them in a multitude of different cellular mechanisms. In this review, we provide an overview of the structural and biological features of 14-3-3 and the modulation of 14-3-3 PPIs for discovering small molecular inhibitors and stabilizers of 14-3-3 PPIs.

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Semisynthesis and biological evaluation of a cotylenin A mimic derived from fusicoccin A

Cited by 21 publications

References 27 publications

Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products

Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products

Structural Effects of Fusicoccin upon Upregulation of 14‐3‐3‐Phospholigand Interaction and Cytotoxic Activity

14-3-3: A Case Study in PPI Modulation

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