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Bioorganic & Medicinal Chemistry Letters Oct 2021Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four...
Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.
Topics: Anti-HIV Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; HIV-1; Humans; Molecular Structure; Phorbol Esters; Structure-Activity Relationship; Virus Replication
PubMed: 34403728
DOI: 10.1016/j.bmcl.2021.128319 -
Molecular Pharmacology Apr 2002In recent years, there have been great advances in our understanding of the pharmacology and biology of the receptors for the phorbol ester tumor promoters and the... (Review)
Review
In recent years, there have been great advances in our understanding of the pharmacology and biology of the receptors for the phorbol ester tumor promoters and the second messenger diacylglycerol (DAG). The traditional view of protein kinase C (PKC) as the sole receptor for the phorbol esters has been challenged with the discovery of proteins unrelated to PKC that bind phorbol esters with high affinity, suggesting a high degree of complexity in the signaling pathways activated by DAG. These novel "nonkinase" phorbol ester receptors include chimaerins (a family of Rac GTPase activating proteins), RasGRPs (exchange factors for Ras/Rap1), and Munc13 isoforms (scaffolding proteins involved in exocytosis). In all cases, phorbol ester binding occurs at the single C1 domain present in these proteins and, as in PKC isozymes, ligand binding is a phospholipid-dependent event. Moreover, the novel phorbol ester receptors are also subject to subcellular redistribution or "translocation" by phorbol esters, leading to their association to different effector and/or regulatory molecules. Clearly, the use of phorbol esters as specific activators of PKC in cellular models is questionable. Alternative pharmacological and molecular approaches are therefore needed to dissect the involvement of each receptor class as a mediator of phorbol ester/DAG responses.
Topics: Animals; Caenorhabditis elegans Proteins; Carrier Proteins; Enzyme Activation; Humans; Models, Molecular; Phorbol Esters; Protein Kinase C; Protein Structure, Tertiary; Receptors, Drug
PubMed: 11901214
DOI: 10.1124/mol.61.4.759 -
Journal of Biomedical Science Mar 2006Exposure of cells to phorbol ester activates protein kinase C (PKC) to induce apoptosis or differentiation, depending on the cellular context. In erythroblastic cell... (Review)
Review
Exposure of cells to phorbol ester activates protein kinase C (PKC) to induce apoptosis or differentiation, depending on the cellular context. In erythroblastic cell lines, TF-1 and D2, upregulation of the RhoA signaling promotes phorbol ester-induced apoptosis through activating Rho-associated kinase (ROCK)/phosphorylation of myosin light chain (MLC), thus generating membrane contraction force. As a result, cell adhesion is inhibited and death receptor-mediated death pathway is activated in these cells with a concurrent changes in nucleocytoplasmic signaling for protein trafficking. A microtubule-regulated GEF-H1, which is a specific RhoA activator, was identified to contribute to RhoA activation in these cells. Thus, a cytoskeleton-regulated RhoA signaling cooperates with PKC activation constitutes a cellular context to determine the cell fate in response to phorbol ester stimulation.
Topics: Apoptosis; Cell Line; Humans; Phorbol Esters; Protein Kinase C; Signal Transduction; rhoA GTP-Binding Protein
PubMed: 16496227
DOI: 10.1007/s11373-005-9056-4 -
Annals of the New York Academy of... 1983The evidence for the multistage nature of tumor promotion in vivo and for multiple subclasses of phorbol ester receptors in vitro argues that multiple mechanisms of... (Review)
Review
The evidence for the multistage nature of tumor promotion in vivo and for multiple subclasses of phorbol ester receptors in vitro argues that multiple mechanisms of tumor promotion exist. The existence of multiple mechanisms suggests that brute force assay for tumor promoters in vivo may be inadequate and that understanding of mechanisms may be essential. The interest in the phorbol esters is not primarily that they are environmental hazards for man, but rather that they provide a probe for phorbol ester receptors. These receptors are found in people, and modulation of their activity may play a role in tumor promotion in man.
Topics: Animals; Caenorhabditis elegans Proteins; Carrier Proteins; Mice; Neoplasms, Experimental; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Protein Kinase C; Receptors, Cell Surface; Receptors, Drug; Skin Neoplasms; Structure-Activity Relationship
PubMed: 6309054
DOI: 10.1111/j.1749-6632.1983.tb47836.x -
Cell Biology International Reports Nov 1983
Review
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Caenorhabditis elegans Proteins; Carrier Proteins; Lymphocyte Activation; Lymphocytes; Mice; Phorbol Esters; Phorbols; Protein Kinase C; Receptors, Cell Surface; Receptors, Drug; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate
PubMed: 6317204
DOI: 10.1016/0309-1651(83)90206-0 -
Princess Takamatsu Symposia 1983Specific phorbol ester receptors are found in the particulate fraction of cells. In addition, cytosol contains a phorbol ester apo-receptor, which requires phospholipids... (Review)
Review
Specific phorbol ester receptors are found in the particulate fraction of cells. In addition, cytosol contains a phorbol ester apo-receptor, which requires phospholipids for reconstitution. The apo-receptor corresponds to protein kinase C, and the quantitatively major membrane receptor appears to be a protein kinase C-phospholipid complex. The ability to reconstitute the phorbol ester apo-receptor into different lipid domains permits analysis of the role of the lipid domain in phorbol ester receptor function. Studies reviewed here indicate that diacylglycerols competitively inhibit phorbol ester binding, consistent with their being the postulated endogenous phorbol ester analogs. Highly lipophilic phorbol esters only inhibit effectively if incorporated into the lipid phase, indicating that the membrane dissolved form of the ligand can be recognized. The binding affinity of [3H]phorbol 12,13-dibutyrate for holo-receptor depends markedly (greater than 20-fold range) on the phospholipid environment, and heterogeneous phorbol ester binding (i.e., curved Scatchard plots) can be generated by use of heterogeneous lipid environments in the reconstitution. The possible existence of other phorbol ester receptors in addition to protein kinase C-phospholipid complexes remains to be resolved.
Topics: Animals; Caenorhabditis elegans Proteins; Carrier Proteins; Cell Membrane; Cytosol; Humans; Kinetics; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Phospholipids; Protein Kinase C; Protein Kinases; Receptors, Drug; Receptors, Immunologic; Solubility; Structure-Activity Relationship; Ultraviolet Rays
PubMed: 6240489
DOI: No ID Found -
Carcinogenesis; a Comprehensive Survey 1982Phorbol esters bind to mouse tissues and chick embryo fibroblasts in a specific, saturable, and reversible fashion. The binding site, located in the membrane fraction,... (Review)
Review
Phorbol esters bind to mouse tissues and chick embryo fibroblasts in a specific, saturable, and reversible fashion. The binding site, located in the membrane fraction, is heat and protease sensitive. Binding can be measured most readily with [3H]PDBu. Binding of [3H]PDBu is of high affinity and is inhibited competitively by nonradioactive phorbol esters; the dissociation constants of the phorbol esters correspond quantitatively to their respective biological and tumor-promoting activities. Of particular significance, highly inflammatory but weakly promoting or nonpromoting diterpene esters are much less potent than PMA. Binding of [3H]PMA has been measured directly. The results confirm that PMA and PDBu interact at the same major high-affinity binding site. [3H]PDBu binding is entropy driven. The equilibrium dissociation constant is independent of temperature, whereas the off-rate is highly temperature dependent. In vivo, specific binding activity increases during embryonic development. It also shows considerable variation among tissues. In the mouse, highest binding activity, 28 pmole/mg, is in the brain (skin, for example, binds 3.9 pmole/mg). Between regions of he brain, 10-fold differences in binding activity are found. The high level of phorbol ester binding in brain suggests that the phorbol ester receptor plays a functional rather than an exclusively information-transducing role in the cell. Growth of cells in the presence of PDBu causes marked down-modulation of phorbol ester receptors. In the GH4C1 rat pituitary cell line, receptor number is decreased by 80% in 24 hr. In membrane preparations, the phorbol ester binding affinity is calcium sensitive. It has been speculated that endogenous ligands interacting at the phorbol ester receptor may exist. The finding that the supernatant fraction from boiled or acidified brain inhibits [3H]PDBu binding is therefore exciting.
Topics: Animals; Biological Evolution; Brain; Caenorhabditis elegans Proteins; Calcium; Carcinogens; Carrier Proteins; Cell Membrane; Cells, Cultured; Humans; Kinetics; Mice; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Protein Kinase C; Receptors, Drug; Skin; Spleen; Structure-Activity Relationship; Temperature; Tetradecanoylphorbol Acetate; Thermodynamics
PubMed: 7039833
DOI: No ID Found -
Molecular Carcinogenesis May 2000In addition to the well-characterized interaction with classical and novel protein kinase C (PKC) isozymes, the phorbol ester tumor promoters bind to other receptors... (Review)
Review
In addition to the well-characterized interaction with classical and novel protein kinase C (PKC) isozymes, the phorbol ester tumor promoters bind to other receptors lacking kinase activity. Among these novel phorbol ester receptors, two families of proteins may play a role in the regulation of cell growth and malignant transformation: chimaerins and ras guanyl-releasing protein (ras-GRP). These proteins possess a single copy of the C1 domain that is involved in binding of phorbol esters and the lipid second messenger diacylglycerol. Four isoforms of chimaerins (alpha1-, alpha2-, beta1-, and beta2-chimaerins) have been isolated to-date, all of them possessing GTPase-activating protein activity for Rac, a small GTP-binding protein that controls actin cytoskeleton organization, cell-cycle progression, adhesion, and migration. Ras-GRP is a guanine nucleotide exchange factor for ras and promotes malignant transformation in fibroblasts in a phorbol ester-dependent manner. The C1 domain in Ras-GRP may, therefore, have a dominant role in Ras-GRP activation and is essential for phorbol ester-dependent activation of downstream effectors of ras, i.e., the mitogen-activated protein kinase cascade. Thus, a novel concept emerges in which phorbol esters may exert cellular responses through pathways not involving phorbol ester-responsive PKC isozymes. The discovery of "nonPKC" phorbol ester receptors adds an additional level of complexity to the understanding of phorbol ester effects and the molecular mechanisms of carcinogenesis.
Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; DNA-Binding Proteins; Guanine Nucleotide Exchange Factors; Humans; Isoenzymes; Phorbol Esters; Protein Kinase C; Receptors, Cell Surface; Signal Transduction
PubMed: 10820483
DOI: 10.1002/(sici)1098-2744(200005)28:1<5::aid-mc2>3.0.co;2-g -
International Journal of Molecular... Mar 2016The Aquilaria malaccensis (Thymelaeaceae) tree is a source of precious fragrant resin, called agarwood, which is widely used in traditional medicines in East Asia...
The Aquilaria malaccensis (Thymelaeaceae) tree is a source of precious fragrant resin, called agarwood, which is widely used in traditional medicines in East Asia against diseases such as asthma. In our continuous search for active natural products, A. malaccensis seeds ethanolic extract demonstrated antiallergic effect with an IC50 value less than 1 µg/mL. Therefore, the present research aimed to purify and identify the antiallergic principle of A. malaccensis through a bioactivity-guided fractionation approach. We found that phorbol ester-rich fraction was responsible for the antiallergic activity of A. malaccensis seeds. One new active phorbol ester, 12-O-(2Z,4E,6E)-tetradeca-2,4,6-trienoylphorbol-13-acetate, aquimavitalin (1) was isolated. The structure of 1 was assigned by means of 1D and 2D NMR data and high-resolution mass spectrometry (HR-MS). Aquimavitalin (1) showed strong inhibitory activity in A23187- and antigen-induced degranulation assay with IC50 values of 1.7 and 11 nM, respectively, with a therapeutic index up to 71,000. The antiallergic activities of A. malaccensis seeds and aquimavitalin (1) have never been revealed before. The results indicated that A. malaccensis seeds and the pure compound have the potential for use in the treatment of allergy.
Topics: Animals; Anti-Allergic Agents; Cell Line, Tumor; Phorbol Esters; Plant Extracts; Rats; Seeds; Thymelaeaceae
PubMed: 27007372
DOI: 10.3390/ijms17030398 -
Journal of Asian Natural Products... Dec 2017Phytochemical investigation of the ethanol extract from the twigs and leaves of Croton tiglium led to the isolation of two new phorbol esters (1-2) and seven known ones...
Phytochemical investigation of the ethanol extract from the twigs and leaves of Croton tiglium led to the isolation of two new phorbol esters (1-2) and seven known ones (3-9). Their structures were elucidated by the analyses of extensive spectroscopic data (IR, MS, and 1D and 2D NMR) and comparing with related compounds. Meanwhile, compounds 1-9 were determined for their cytotoxic activities on human lung cancer cell line A549. Among them, 1-2 were inactive against the cell line A549 (IC > 100 μM), but compounds 3 and 7 showed weak activities.
Topics: Antineoplastic Agents, Phytogenic; Croton; Diterpenes; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phorbol Esters; Plant Components, Aerial
PubMed: 28374632
DOI: 10.1080/10286020.2017.1307836