Structure–activity studies at position 27 of aplog-1, a simplified analog of debromoaplysiatoxin with anti-proliferative activity

Hanaki, Yusuke; Kikumori, Masayuki; Ueno, Sayo; Tokuda, Harukuni; Suzuki, Nobutaka; Irie, Kazuhiro

doi:10.1016/j.tet.2013.02.008

Cited by 18 publications

(11 citation statements)

References 41 publications

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“…The concentration required to cause 50% inhibition (IC 50 Table 1 lists the K i value of 3 for δ-C1B along with those of aplog-1 and its 27-methyl and 27-methoxy derivatives (1 and 2). As previously reported, 21,33) the stereochemistry at position 27 was critical for PKC binding, and the free hydroxyl group at position 27 was indispensable. Although the amide analog 3 fulfilled these structural requirements at position 27 for PKCδ binding, the affinity of 3 (K i = 520 nM) was approximately two orders of magnitude weaker than that of aplog-1 (K i = 7.4 nM).…”

Section: Resultssupporting

confidence: 61%

“…Aplog-1 and its C-27 derivatives (1 and 2) induced EA production more weakly than the potent tumor promoter TPA. The ability of 3 to induce EA production was weaker than those of 1 and 2 without the ability to bind to PKC isozymes 21,33) (Fig. 3).…”

Section: Resultsmentioning

confidence: 92%

“…20) To examine the contribution of PKCδ to the anti-proliferative activity of aplog-1, we recently synthesized 27-methyl and 27-methoxy derivatives (1, 2) that lacked the ability to bind to PKCδ and evaluated their anti-proliferative activities against 39 human cancer cell lines. 21) Compounds 1 and 2 only exhibited weak anti-proliferative activities against all the human cancer cell lines tested, 21) suggesting that the activation of PKCδ was involved in growth inhibitory activities against several cancer cell lines that were at least sensitive to aplog-1. The next step is to evaluate and improve the anti-proliferative activity of aplog-1 in vivo.…”

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confidence: 99%

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Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities

Hanaki

Yanagita

Sugahara

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (3), in which the C-1 ester group was replaced with an amide group, to improve chemical stability in vivo. Unfortunately, 3 exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10−4 M. A conformational analysis and density functional theory calculations indicated that the stable conformation of 3 differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (1, 2) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10−4 M, 3 may be an inactive control to identify the target proteins of aplogs.

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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 92%

mentioning

confidence: 99%

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Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities

Hanaki

Yanagita

Sugahara

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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“…Upon the treatment of PKCδ with 7 or bryo‐1, PKCδ translocated from the cytosol to the nuclear membrane and perinuclear region in CHO‐K1 (Chinese hamster ovary) cells, while TPA induced mainly translocation to the plasma membrane. To examine the correlation between PKCδ binding and anti‐proliferative activity, we prepared three derivatives of aplog‐1 ( 21 – 23 ) that differ in the ability to bind PKCδ . These are 27‐( R )‐methyl‐aplog‐1 ( 21 ), which has an absolute configuration at position 27 that is the same as that of DAT at position 30, the 27‐epimer of 21 ( 22 ), and 27‐ O ‐methyl‐aplog‐1 ( 23 ) (Figure ).…”

Section: Synthesis Of Aplog‐1 and Its Congenersmentioning

confidence: 99%

Synthesis and Biological Activities of Simplified Analogs of the NaturalPKCLigands, Bryostatin‐1 and Aplysiatoxin

Irie

Yanagita

2014

The Chemical Record

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Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is a potent PKC activator with little tumor-promoting activity. Numerous investigations have suggested bryo-1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo-1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo-1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo-1 surrogates. We have recently identified 10-methyl-aplog-1 (26), a simplified analog of tumor-promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo-1 and ATX, to develop potential medicinal leads.

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“…27.7), with potent antiproliferative properties as potential anticancer agents [95][96][97][98][99][100][101][102][103]. These synthetic analogues have been shown to inhibit the action of tumor promotors as well as prevent growth of cancer cells in similar ways to bryostatin 1.…”

Section: Aplysiatoxinsmentioning

confidence: 99%

Molecular Targets of Anticancer Agents from Filamentous Marine Cyanobacteria

Tan

Gupta

2014

Handbook of Anticancer Drugs From Marine Origin

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The prokaryotic marine cyanobacteria, especially the filamentous forms, are known to produce a plethora of structurally unique natural products. A majority of these molecules are nitrogen-containing, belonging to the hybrid polyketide-polypeptide structural class. Various activities of clinical significance have been attributed to these molecules, ranging from anticancer, neuromodulating to antiprotozoal properties. Particularly in the area of cancer therapy, a number of potent marine cyanobacterial compounds, including dolastatins 10, 15, and largazole, have been identified as anticancer drug leads and are being further developed synthetically for clinical usage. The high potencies of these compounds are due to their exquisite interactions or interference with cellular pathways, specific macromolecules, or enzymes, such as the JAK-STAT signaling pathway, histone deacetylase, proteasome, protein kinase C, actin and microtubule filaments. This mini review covers more than 90 references and features more than 40 anticancer compounds, consisting of marine cyanobacterial natural products and their synthetic analogues. Biological data of these compounds are discussed based on their molecular targets.

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Structure–activity studies at position 27 of aplog-1, a simplified analog of debromoaplysiatoxin with anti-proliferative activity

Cited by 18 publications

References 41 publications

Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities

Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities

Synthesis and Biological Activities of Simplified Analogs of the NaturalPKCLigands, Bryostatin‐1 and Aplysiatoxin

Molecular Targets of Anticancer Agents from Filamentous Marine Cyanobacteria

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