Investigation of the Antitumor Activity of Podocarpic Acid Derivatives

Cutfield J.F., Waters T.N., Clark G.R.

The crystal and molecular structures of the title compounds have been determined by X-ray diffraction methods from photographic data by the heavy-atom method; the absolute configuration was established for the second named. Crystals of the former (II) are tetragonal, a= 12·54, c= 23·97, A, space group P41212; the structure was refined by least squares to R 0·088. The latter (III) is triclinic, a= 6·20, b= 7·73, c= 10·79 A, α= 97·0, β= 79·3, γ= 104·6°, space group P1; refined to R 0·064. In (II) ring A has a chair conformation with a trans A/B ring fusion; ring B has an approximate boat conformation and the bromine atom has the α-configuration. The bromine is in the same configuration in compound (III) and ring A also adopts the chair conformation. There is trans A/B ring fusion with ring B somewhat distorted but describable as a ‘half-boat’. The stereochemistries at asymmetric centres confirm earlier evidence. There is considerable variation in detailed conformation, however, and a comparison between these compounds and with the molecular structure of methyl 6α-bromo-12-methoxy-7-oxopodocarpa-8,11,13-trien-16-oate leads to the view that steric rather than electronic factors are largely responsible for the path of bromine attack.

Parish E.J., Miles D.H.

Parish E.J., Miles D.H.

Galbraith M.N., Horn D.H., Sasse J.M.

Galbraith M.N., Horn D.H., Sasse J.M., Adamson D.

Lickei A.E., Rieke A.C., Wheeler D.M.

Wenkert E., Fuchs A., McChesney J.D.

Bose A.K., Manhas M.S., Cambie R.C.

Wenkert E., Beak P., Carney R.W., Chamberlin J.W., Johnston D.B., Roth C.D., Tahara A.

The lithium aluminum hydride reduction of nitriles in the aromatic resin acid series to aldimines and the conversion of the products to other derivatives are described. The effect of the stereochemistry of the nitriles on the rate of reduction is noted. The transformation of dehydroabietane into a dehydro product is indicated. The syntheses of a desoxydecarboxy-5,6-dehydro-7-keto derivative of podocarpic acid and its optical antipode are discussed. The stereochemistry of hydrogenation of 5,6-dehydro derivatives of podocarpic acid is reported. The effect of a 7-keto group on the rate of hydrolysis of methyl esters of aromatic resin acids is illustrated. The reactions of 6-bromo-7-keto derivatives of methyl podocarpate with bases are portrayed.

Nadana G.R., Rajesh C., Kavitha A., Sivakumar P., Sridevi G., Palanichelvam K.

Coelomic fluid (CF) of earthworms, Eudrilus eugeniae, collected by cold stress method (cold CF) was tested for its potential in different growth parameters such as seed germination, lengths of shoot, root and seedlings and vigor index in Oryza sativa L. subsp. indica. Gibberellic acid (GA) was used as a control to compare with cold CF. Rate of seed germination and length of roots were better in CF-treated seedlings. Other growth parameters were improved by CF when compared to control, but lesser or closer to the levels induced by GA. Bioassays with detached leaves from rice plants and the fungal pathogen Rhizoctonia solani revealed that the disease index was reduced in CF-treated rice plants. Liquid chromatography and mass spectrometry (LC–MS)​ analysis of CF suggested the presence of compounds with pesticidal, insecticidal, antifungal and plant hormone properties. Plant hormone derivative, indole-3-acetyl-L-valine, from CF of earthworms is reported here for the first time. Our results provide knowledge on developing new environmentally safe compounds to improve agriculture from organic wastes. The biological roles of metabolites in CF on growth parameters of rice and resistance towards R. solani are discussed.

S. J. R.D., Kumar B. P.

Background: Balaguluchyadi kashayam, a polyherbal Ayurvedic decoction prepared from Sidacordifolia L., Tinospora cordifolia (Willd.) Miers, and Cedrusdeodara (Roxb. ex D.Don) G.Don, is used in Ayurveda for the treatment of chronic inflammatory conditions. Although this herbal decoction has been used for a long period for treating chronic inflammatory conditions, the mechanism of action of the decoction in reducing inflammatory conditions associated with chronic inflammation has not been clearly understood. Mass spectroscopy-based identification of bioactive molecules present in the decoction and its interaction with enzymes/proteins involved in the pathogenesis of chronic inflammation has been carried and reported in this study. Introduction: Polyherbalism is one of the major principles of Ayurveda. Various phytoconstituents with different activities in the polyherbal decoction act on multi targets of a wide range of diseases. Balaguluchyadi kashayam is a polyherbal decoction prescribed for chronic inflammatory etiologies and the present study aims to evaluate the binding potential of the compounds, identified from Balaguluchyadi kashayam to enzymes/proteins involved in the development and progression of chronic inflammation. Methods: The bioactive compounds present in the Balaguluchyadi Kashayam fractions were extracted by preparative HPLC and identified using UPLC MS Q-TOF. The physicochemical characteristics and ADMET properties of the compounds were calculated using Mol soft, Swiss ADME and OSIRIS data warrior software. Then the binding interactions between the molecules and the proinflammatory mediators such as 5 Lipoxygenase, Cyclooxygenase 2, Tumor necrosis factoralpha convertase enzyme (TACE) and Caspase 1 were determined using molecular docking software Auto Dock 4.0 (http://autodock.scripps.edu/downloads). Results: The identified bioactive molecules in the decoction showed a good binding affinity towards the enzymes/proteins involved in the development and progression of chronic inflammation compared to the binding affinity of known inhibitors/drugs to the respective enzymes/proteins. Conclusion: The bioactive molecules identified in Balaguluchyadi Kashayam could be developed as potential therapeutic molecules against enzymes/proteins involved in the development and progression of chronic inflammation.

Motta L.B., Furlan C.M., Santos D.Y., Salatino M.L., Negri G., de Carvalho J.E., Monteiro P.A., Ruiz A.L., Caruzo M.B., Salatino A.

Several Croton species have been used in traditional medicine and contain substances active against cancer, such as diterpenoids and alkaloids. Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. The main goal of this study was to characterize the main constituents of the leaf extracts of C. sphaerogynus and evaluate their in vitro antiproliferative activity against tumor cell lines. Hexane, dichloromethane and methanol extracts of leaves were analyzed by GC/MS and evaluated for their in vitro antiproliferative activity on the cell lines 786-0 (kidney), HT-29 (colon), K562 (leukemia), NCI-ADR/RES (drug resistant ovary), NCI-H460 (lung), MCF-7 (mammary), PC-3 (prostate), OVCAR-3 (ovary), U251 (glioma) and UACC-62 (melanoma). Relevant constituents in dichloromethane and hexane extracts were abietane, podocarpane and clerodane type furano diterpenes. Dicloromethane and hexane extracts exhibited activity against NCI-H460 (GI 50 0.26 μg/mL and 0.33 μg/mL, respectively) and K562 (GI 50 0.60 μg/mL and 50 0.86) than hexane and methanol extracts (mean log GI 50 1.26 and 1.49, respectively). The antiproliferative activity observed in the present work is probably accounted for by the abietane and/or podocarpane diterpenes.

Nguyen D.M., Miles D.H.

Copper iodide was employed as an efficient catalyst for the synthesis of 1,2,3-triazole derivatives of podocarpic acid at room temperature through “click” chemistry cycloaddition reactions of methyl O-propargylpodocarpate and propargyl O-propargylpodocarpate with azides.

Baraka H.

Podocarpic acid was metabolized by Mucor ramannianus ATCC 9628, and Beauveria bassiana ATCC 7159 to afford two new metabolites, 2 alpha-hydroxy podocarpic acid and 11-hydroxy podocarpic acid, along with the known metabolite 13-hydroxy podocarbic acid. The identity of these metabolites was verified using different spectral methods. The antioxidant activity of the metabolites was tested, and comparable results to those observed for ascorbic acid were obtained.

Nicolaou K.C., Gray D.L., Tae J.

A number of naturally occurring substances, including hamigerans, contain ring systems which are fused to an aromatic nucleus. A general and streamlined method for the construction of such benzannulated bi- and polycyclic carbon frameworks has been developed, and its scope and limitations were explored. On the basis of the photoenolization of substituted benzaldehydes and subsequent Diels-Alder (PEDA) trapping of the generated hydroxy-o-quinodimethanes, this method was optimized to set the stage for the total synthesis of several naturally occurring members of the hamigeran class. Specifically, the developed synthetic technology served as the centerpiece process for the successful asymmetric synthesis of hamigerans A (2), B (3), and E (7). In addition to the PEDA reactions, several other novel reaction processes are described, including a high-yielding decarbonylative ring contraction and an oxidative decarboxylation of a hydroxyl beta-keto ester to afford an alpha-diketone. A number of analogues of these biologically active natural products were also prepared by application of the developed technology.

Roy A., Paul T., Drew M.G., Mukherjee D.

A stereocontrolled total synthesis of methyl (±)-O-methyl podocarpate ( 4 ) has been successfully accomplished using the trans-fused diester 21 as a key intermediate. Intramolecular Michael reaction of the enone-diester 18 afforded the cis-fused keto-diester 19 in high yield which was stereoselectively converted into 21 via the enone 20 .

Staschke K.A., Hatch S.D., Tang J.C., Hornback W.J., Munroe J.E., Colacino J.M., Muesing M.A.

Entry of influenza virus into the host cell is dependent on the fusion of the viral envelope with the endosomal membrane and is mediated by a low-pH-induced change of the viral hemagglutinin (HA) to a conformation that is fusogenic. A compound related to podocarpic acid (180299) was identified that inhibits multicycle replication of influenza A/Kawasaki/86 (H1N1) virus in culture. Treatment of Madin-Darby canine kidney (MDCK) cells with 180299 at 1 h before infection resulted in the inhibition of viral protein synthesis. Addition of 20 microgram of 180299/ml at 1 h p.i. had no effect, indicating that 180299 affects an early step of the influenza viral replication cycle. Genetic analysis of reassortants between sensitive and resistant viruses demonstrated that hemagglutinin (HA) conferred the 180299-resistant (180299(r)) phenotype. Twelve independent isolates of influenza A/Kawasaki/86 were selected for resistance to 180299, and sequence analysis revealed that each of these viruses contained amino acid substitutions in the HA. These mutations are dispersed throughout the HA primary amino acid sequence and cluster in one of two regions: the interface between HA1 and HA2 and in a region near the fusion domain of HA2. When compared with the parent virus, the pH-of-inactivation of the resistant mutants was increased by 0.3 to 0.6 pH unit, suggesting that the mutant HAs undergo the conformational change at an elevated pH. Fusion of human erythrocytes to MDCK cells infected with parent influenza A/Kawasaki/86 was inhibited by 180299 (0.1-10 microgram/ml) in a concentration-dependent manner, whereas fusion of erythrocytes to MDCK cells infected with 180299(r) mutants was not affected. These results suggest that 180299 interacts with the neutral pH conformation of influenza A HA and prevents the low-pH-induced change of HA to its fusogenic conformation.

Cambie R.C., Metzler M.R., Rickard C.E., Rutledge P.S., Woodgate P.D.

Reaction of tetracarbonylmanganese(I) complexes derived from podocarpic acid ( 1 ) with electrophilic bromine or iodine in CCl 4 leads to 14-halogenated derivatives inaccessible by direct halogenation. Similar reactions in protic solvents lead to the formation of γ-lactones in high yield. The structure of one of these was established unequivocally by X-ray crystallography. Attempted oxidation of the CMn bond with a number of reagents proved generally to be unsuccessful.

Parish E.J., Chitrakorn S., Wei T.

Abstract Pyridinium chlorochromate, in refluxing methylene chloride, has been found to be an effective reagent for allylic and benzylic oxidations of activated methylene groups to yield the corresponding unsaturated ketones.

Parish E.J., McKeen G.G., Miles D.H.

(1985). LOW TEMPERATURE OZONOLYSIS OF METHYL O-METHYL PODOCARPATE. Organic Preparations and Procedures International: Vol. 17, No. 2, pp. 143-146.