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Journal of Natural Products Sep 2018An alternative procedure for isolation of 4β-phorbol from seeds of Croton tiglium has been developed, and an artifact containing a furan ring formed by rearrangement of...
An alternative procedure for isolation of 4β-phorbol from seeds of Croton tiglium has been developed, and an artifact containing a furan ring formed by rearrangement of 12,13,20- O-triacylated phorbol derivatives into (6b S,7 R,8 R,8a S)-2-(hydroxymethyl)-5,7,9,9-tetramethyl-3,7,8,9,9a,9b-hexahydrocyclopropa[3',4']benzo[1',2':3,4]cyclohepta[1,2- b]furan-6b,8,8a-triol (8a) has been characterized. A mechanism involving an oxidative rearrangement and a decarboxylation for formation of the artifact is proposed.
Topics: Croton; Phorbols; Seeds
PubMed: 30216064
DOI: 10.1021/acs.jnatprod.8b00607 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Sep 2023Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According... (Review)
Review
Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According to the different functional groups, they can be classified into types of phorbol esters, C-4 deoxyphorbol esters, C-12 deoxyphorbol esters, C-16 or C-17 substituted phorbol esters and others. Most of them present promising antiviral activities and cytotoxic activities and are expected to be developed as candidates for anti-AIDS, anti-tuberculosis, and anti-tumor clinical trials, demonstrating great potential for the application in healthcare. This paper reviews 115 novel tigliane-type diterpenoids discovered since 2013 and summarize their chemical structures and bioactivities, aiming to lay a foundation for further development and utilization of these compounds and provide new ideas for the development of clinical drugs.
Topics: Phorbols; Molecular Structure; Diterpenes; Antiviral Agents; Phorbol Esters
PubMed: 37802801
DOI: 10.19540/j.cnki.cjcmm.20230427.201 -
Bioorganic & Medicinal Chemistry Letters Apr 2020TRPV4 is a ubiquitously expressed, non-selective cation channel activated by a range of stimuli including hypotonicity, temperature, pH, stretch and endogenous ligands.... (Review)
Review
TRPV4 is a ubiquitously expressed, non-selective cation channel activated by a range of stimuli including hypotonicity, temperature, pH, stretch and endogenous ligands. Agents that modulate TRPV4 are sought as potential therapeutics for the treatment of many diseases including osteoarthritis, respiratory illnesses, gastrointestinal disorders, pain and congestive heart failure. In recent years, significant advances in TRPV4 drug discovery have been realized as at least seven novel TRPV4 agonist or antagonist templates were reported and the first selective TRPV4 antagonist was evaluated in early clinical trials.
Topics: Biological Products; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Phorbols; TRPV Cation Channels
PubMed: 32063431
DOI: 10.1016/j.bmcl.2020.127022 -
Carcinogenesis 1982Autoradiography has been used to study the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), 4-O-methyl TPA, and phorbol on metabolic cooperation between human...
Autoradiography has been used to study the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), 4-O-methyl TPA, and phorbol on metabolic cooperation between human diploid fibroblasts. When the donors, hypoxanthine-guanine phosphoribosyl transferase+ (HGPRT+) cells, and recipients, HGPRT- cells, were plated together in the presence of [3H]hypoxanthine and either 4-O-methyl TPA or phorbol, nearly all interactions that developed in 4 h were positive for metabolic cooperation whereas when high concentrations of TPA were used, the number of positive interactions was significantly less than the control. If the phorbol analogs were added after the donors and recipients had made contact, the number of positive interactions was the same as the control in all cases. However, although primary recipients in the cultures that had been treated with phorbol had the same number of grains as those in the control, primary recipients in cultures that had been treated with TPA or high concentrations of 4-O-methyl TPA had significantly fewer grains than those in the control. TPA treatment for 4 h had no effect on total [3H]hypoxanthine incorporation or incorporation into acid-soluble and acid-insoluble fractions. Thus, the effect of TPA on metabolic cooperation is interpreted as a reduction in the transfer of [3H]nucleotides and is an indication of an interference with intercellular communication.
Topics: Autoradiography; Cell Communication; Cell Line; Fibroblasts; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Mutation; Phorbols; Tetradecanoylphorbol Acetate; Tritium
PubMed: 7172420
DOI: 10.1093/carcin/3.10.1207 -
Chinese Journal of Natural Medicines Feb 2024In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol...
In this study, 37 derivatives of phorbol esters were synthesized and their anti-HIV-1 activities evaluated, building upon our previous synthesis of 51 phorbol derivatives. 12-Para-electron-acceptor-trans-cinnamoyl-13-decanoyl phorbol derivatives stood out, demonstrating remarkable anti-HIV-1 activities and inhibitory effects on syncytia formation. These derivatives exhibited a higher safety index compared with the positive control drug. Among them, 12-(trans-4-fluorocinnamoyl)-13-decanoyl phorbol, designated as compound 3c, exhibited the most potent anti-HIV-1 activity (EC 2.9 nmol·L, CC/EC 11 117.24) and significantly inhibited the formation of syncytium (EC 7.0 nmol·L, CC/EC 4891.43). Moreover, compound 3c is hypothesized to act both as an HIV-1 entry inhibitor and as an HIV-1 reverse transcriptase inhibitor. Isothermal titration calorimetry and molecular docking studies indicated that compound 3c may also function as a natural activator of protein kinase C (PKC). Therefore, compound 3c emerges as a potential candidate for developing new anti-HIV drugs.
Topics: Molecular Docking Simulation; Anti-HIV Agents; Phorbols; Phorbol Esters; HIV Reverse Transcriptase; Structure-Activity Relationship
PubMed: 38342567
DOI: 10.1016/S1875-5364(24)60587-X -
Nature Apr 2016Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to...
Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes, germacrenes, taxanes and ingenanes have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C-C bond constructions and C-H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.
Topics: Bicyclic Monoterpenes; Biological Products; Chemistry Techniques, Synthetic; Diterpenes; Molecular Structure; Monoterpenes; Oxygen; Phorbol Esters; Phorbols; Stereoisomerism
PubMed: 27007853
DOI: 10.1038/nature17153 -
Proceedings of the National Academy of... Sep 1986Because brief exposure to phorbol esters renders normal cells vulnerable to deformation and cytolysis by lymphocytes, it was postulated that these tumor promoters might...
Because brief exposure to phorbol esters renders normal cells vulnerable to deformation and cytolysis by lymphocytes, it was postulated that these tumor promoters might cause a hitherto unrecognized physical alteration in membrane architecture. To investigate this possibility, four tissue culture cell lines (K-562 erythroleukemia cells, melanoma cells, N1121 adult fibroblasts, and normal fetal fibroblasts) and three blood cell types (lymphocytes, monocytes, and platelets) were subjected to freeze-fracture analysis before and after brief treatment with phorbol myristate acetate. Phorbol myristate acetate caused a 50% reduction of intramembranous particles associated with the external leaflet (E face) of the plasma membrane of every cell except platelets. In contrast, no change in size or number of intramembranous particles associated with the protoplasmic membrane leaflet (P face) was evident. Since the platelet membrane is known to be turned "inside out," as regards the partition coefficient of the intramembranous particles, the disparity between the results obtained with platelets and other cells may serve to determine the nature of intramembranous particles affected by phorbols. Also, since phorbols affect primarily glycolipids and/or glycoproteins anchored in the external membrane leaflet, these findings may provide a useful tool for future exploration of membrane structure.
Topics: Cell Membrane; Freeze Fracturing; Humans; Phorbols; Tetradecanoylphorbol Acetate
PubMed: 3462729
DOI: 10.1073/pnas.83.18.6829 -
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 -
Science (New York, N.Y.) Feb 1976Extracts of Euphorbia esula L. and Croton tiglium L., two members of the Euphorbiaceae which have been used widely in folk medicine for treating cancers, showed...
Extracts of Euphorbia esula L. and Croton tiglium L., two members of the Euphorbiaceae which have been used widely in folk medicine for treating cancers, showed antileukemic activity against the P-388 lymphocytic leukemia in mice. Systematic fractionation of the extract of Euphorbia esula L. led to characterization of a major antileukemic component as the new diterpenoid diester, ingenol 3,20-dibenzoate. Similar fractionation of Croton oil led to characterization of phorbol 12-tiglate 13-decanoate as an active principle.
Topics: Animals; Antineoplastic Agents; Benzoates; Croton Oil; Diterpenes; Leukemia, Experimental; Mice; Phorbol Esters; Phorbols; Plants, Medicinal
PubMed: 1251193
DOI: 10.1126/science.1251193 -
Nature Oct 1979
Topics: Animals; Antigens, Surface; Cell Adhesion; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Dose-Response Relationship, Drug; Epidermal Cells; Epidermis; Mice; Phorbol Esters; Phorbols; Structure-Activity Relationship; Tetradecanoylphorbol Acetate
PubMed: 492322
DOI: 10.1038/281589a0