Biological activity of 26-succinylbryostatin 1

Bignami, Gary S.; Wagner, Fred; Grothaus, Paul G.; Rustagi, Pradip K.; Davis, Dana; Kraft, Andrew S.

doi:10.1016/0167-4889(96)00018-3

Cited by 12 publications

(13 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 MRM-LC-MS/MS allowed for sensitive detection (>0.009 ng/μL) of the sodiated bryostatin 1 ion at m / z 927.4, consistent with previous reports. 42 AH vaults were co-incubated for 30 min at 4 °C with bryostatin 1 and subsequently collected from solution using ultracentrifugation at 100000 g .…”

Section: Resultssupporting

confidence: 89%

Bioengineered Vaults: Self-Assembling Protein Shell–Lipophilic Core Nanoparticles for Drug Delivery

et al. 2014

View full text Add to dashboard Cite

We report a novel approach to a new class of bioengineered, monodispersed, self-assembling vault nanoparticles consisting of a protein shell exterior with a lipophilic core interior designed for drug and probe delivery. Recombinant vaults were engineered to contain a small amphipathic α-helix derived from the nonstructural protein 5A of hepatitis C virus, thereby creating within the vault lumen a lipophilic microenvironment into which lipophilic compounds could be reversibly encapsulated. Multiple types of electron microscopy showed that attachment of this peptide resulted in larger than expected additional mass internalized within the vault lumen attributable to incorporation of host lipid membrane constituents spanning the vault waist (>35 nm). These bioengineered lipophilic vaults reversibly associate with a sample set of therapeutic compounds, including all-trans retinoic acid, amphotericin B, and bryostatin 1, incorporating hundreds to thousands of drug molecules per vault nanoparticle. Bryostatin 1 is of particular therapeutic interest because of its ability to potently induce expression of latent HIV, thus representing a preclinical lead in efforts to eradicate HIV/AIDS. Vaults loaded with bryostatin 1 released free drug, resulting in activation of HIV from provirus latency in vitro and induction of CD69 biomarker expression following intravenous injection into mice. The ability to preferentially and reversibly encapsulate lipophilic compounds into these novel bioengineered vault nanoparticles greatly advances their potential use as drug delivery systems.

show abstract

Section: Resultssupporting

confidence: 89%

Bioengineered Vaults: Self-Assembling Protein Shell–Lipophilic Core Nanoparticles for Drug Delivery

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Compound 8 lacks the phenolic hydroxyl group, and 9 lacks both. The calculated log P values (partition coefficients between n ‐octanol and water) of TPA, teleocidin B‐4, and ATX exceed 5.0, while those of these analogs are less than 3.0, which are values comparable to the measured log P value of bryo‐1 (2.9) …”

Section: Development and Biological Activities Of The Simplified Analsupporting

confidence: 54%

“…Major differences between bryo‐1 and tumor promoters like TPA and teleocidin B‐4 are the hydrophobicity/hydrophilicity of the molecules. TPA and teleocidin B‐4 are highly hydrophobic molecules (calculated log P > 6.0) while bryo‐1 is hydrophilic (log P = 2.9) . The hydrophobicity of phorbol or teleocidin derivatives correlated well with their binding potency to PKC isozymes as well as their tumor‐promoting activity .…”

Section: Bryostatin‐1 a Unique Pkc Activator With Anti‐proliferativementioning

confidence: 97%

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

Irie

Yanagita

2014

The Chemical Record

View full text Add to dashboard Cite

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.

show abstract

“…These values bracket the reported experimentally determined LogP value of bryostatin 1, which was 2.88. [15] As a further criterion, we tried to select compounds with divergent structural features or unusual patterns of biological activity. Prostratin is anti-tumor promoting [16] and has been suggested to be of therapeutic utility for abolition of HIV latency.…”

Section: Resultsmentioning

confidence: 99%

Some Phorbol Esters Might Partially Resemble Bryostatin 1 in their Actions on LNCaP Prostate Cancer Cells and U937 Leukemia Cells

et al. 2011

View full text Add to dashboard Cite

Phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 are both potent protein kinase C (PKC) activators. In LNCaP human prostate cancer cells, PMA induces tumor necrosis factor alpha (TNFα) secretion and inhibits proliferation; bryostatin 1 does not and itself blocks the response to PMA. This difference has been attributed to bryostatin 1 not localizing PKCδ to the plasma membrane. Since phorbol ester liphophilicity influences PKCδ localization, we have examined in LNCaP cells a series of phorbol esters and related derivatives spanning some 8 logs in lipophilicity (LogP) to see if any behave like bryostatin 1. The compounds showed marked differences in their effects on proliferation and TNFα secretion. For example, maximal responses for TNFα secretion relative to PMA ranged from 97% for octyl-indolactam V to 24% for phorbol 12,13-dibenzoate. Dose response curves ranged from monophasic for indolactam V to markedly biphasic for sapintoxin D. The divergent patterns of response, however, correlated neither with lipophilicity, with plasma membrane translocation of PKCδ, or with the ability to interact with model membranes. In U937 human leukemia cells, a second system in which PMA and bryostatin 1 have divergent effects, viz. PMA but not bryostatin 1 inhibits proliferation and induces attachment, all the compounds acted like PMA for proliferation but several induced a reduced level or a biphasic dose response curve for attachment. We conclude that active phorbol esters are not all equivalent. Depending on the system, some may partially resemble bryostatin 1 in their behavior, encouraging the concept that bryostatin-like behavior may be obtained from other structural templates.

show abstract

Biological activity of 26-succinylbryostatin 1

Cited by 12 publications

References 25 publications

Bioengineered Vaults: Self-Assembling Protein Shell–Lipophilic Core Nanoparticles for Drug Delivery

Bioengineered Vaults: Self-Assembling Protein Shell–Lipophilic Core Nanoparticles for Drug Delivery

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

Some Phorbol Esters Might Partially Resemble Bryostatin 1 in their Actions on LNCaP Prostate Cancer Cells and U937 Leukemia Cells

Contact Info

Product

Resources

About