Biomedical subjects
Publications and source records attributed to A D Rodríguez.
Two diterpenes, epipolone (1) and epipolol (3), produced by terpenoid pathways leading to a tricarbocyclic structure with an irregular "head to tail" isoprene configuration, have been isolated from the Caribbean marine sponge Epipolasis reiswigi collected in Puerto Rico. The structures of 1 and 3 were elucidated largely by 1D and 2D NMR methods and chemical conversion.
Long-chain alkanols are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral nicotinic acetylcholine receptor (AChR) by binding to one or more specific sites on the AChR. Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica AChR and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed.
Cembranoids are cyclic diterpenoids found in tobacco and in marine invertebrates. The present study established that tobacco cembranoids inhibit behavioral sensitization to nicotine in rats and block several types of nicotine acetylcholine receptors (AChRs). 1) At the behavioral level, rat locomotor activity induced by nicotine was significantly increased after seven daily nicotine injections. This sensitization to nicotine was blocked by mecamylamine (1 mg/kg) and by the cembranoids eunicin, eupalmerin acetate (EUAC), and (4R)-2,7,11-cembratriene-4-6-diol (4R), each at 6 mg/kg. None of these compounds modified locomotor activity of nonsensitized rats. 2) In cells expressing human AChRs, cembranoids blocked carbamoylcholine-induced (86)Rb(+) flux with IC(50) in the low micromolar range. The cell lines used were the SH-EP1-halpha4beta2 cell line heterologously expressing human alpha4beta2-AChR, the SH-SY5Y neuroblastoma line naturally expressing human ganglionic alpha3beta4-AChR, and the TE671/RD cell line naturally expressing embryonic muscle alpha1beta1gammadelta-AChR. The tobacco cembranoids tested were 4R and its diastereoisomer 4S, and marine cembranoids tested were EUAC and 12,13-bisepieupalmerin. 3) At the molecular level, tobacco (4R and 4S) and marine (EUAC) cembranoids blocked binding of the noncompetitive inhibitor [(3)H]tenocyclidine to AChR from Torpedo californica electric organ. IC(50) values were in the submicromolar to low-micromolar range, with 4R displaying an order of magnitude higher potency than its diastereoisomer, 4S.
A method for the synthesis of derivatives of the lead structures euniolide (1), 12,13-bisepieupalmerin (2), and eupalmerin acetate (3) containing tetrahydrofuran and tetrahydropyran ring systems was developed on the basis of alkali-induced intramolecular oxacyclizations. Representatives of the new analogues were submitted to the in vitro antitumor cell-line-screening program of the National Cancer Institute (NCI). While it was shown that a variety of structural modifications are possible, these transformations led typically to nontoxic synthetic cembranoids.
Two new antimycobacterial serrulatane diterpenes, erogorgiaene (3) and 7-hydroxyerogorgiaene (4), and a novel C(40) bisditerpene (5), have been isolated from the West Indian gorgonian octocoral Pseudopterogorgia elisabethae. The structures of compounds 3-5 were determined by spectral (1D and 2D NMR, IR, UV, and HREIMS) analysis.
A recent investigation of the constituents of Eunicea sp. from Colombia and Puerto Rico has provided two novel cembrane glycosides, calyculaglycosides D (6) and E (7), and a new cembranoid diterpene in free form, (+)-nephthenol (4). Metabolites 6 and 7 possess a glycosyl-fused cembrane skeleton with a 1S configuration. Biogenetic considerations have led to a revision of the previously assigned dilophol skeleton of calyculaglycosides A-C, which was confirmed by extensive 2D NMR investigation and a chemical degradation study. Consequently, the true structures for calyculaglycosides A-C are 8-10, respectively, not 1-3. This is the first report of the occurrence of marine diterpene glycosides having a cembrane aglycon.
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From the hexane extract of the West Indian gorgonian Pseudopterogorgia elisabethae, two diterpenes, cumbiasins A (1) and B (2), having a novel tetracyclic carbon skeleton named cumbiane, have been isolated. In addition, we have isolated cumbiasin C (3), a ring cleavage product of cumbiasin B that possesses an unusual carbocyclic framework named seco-cumbiane. The structures and relative configurations of metabolites 1-3 were elucidated by interpretation of overall spectral data, which included 2D NMR correlation methods, IR, UV, and accurate mass measurements (HREI-MS and HRFAB-MS). The carbocyclic skeletons of the cumbiasins are unprecedented and represent new classes of C20 rearranged diterpenes. Cumbiasins A and B display mild in vitro anti-tuberculosis activity.
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The West Indian alcyonacean Pseudopterogorgia bipinnata (Verrill, 1864) is shown to contain a novel bisditerpenoid ether: biskallolide A (2). The structural assignment of 2 was mainly based on 1D and 2D NMR and MS spectral data and was further confirmed by synthesis. The 2-C-alkoxylation of furanopseudopteranes kallolide A (1) and isokallolide A (8) occurs spontaneously in some solvents and involves replacement of the C2 hydroxyl with an alkoxyl group to yield solvolysis products that display net retention of configuration. The facile solvolytic 2-C-acyloxylation of kallolide A was achieved readily under similar circumstances to afford kallolide A acetate (4) as the sole product. Mechanistic details in conversion of alcohols 1 and 8 into various solvolysis products, including dimeric ethers 2 and 9, were investigated in this study. Solvolysis of kallolide A and isokallolide A in [(18)O]-labeled solvent demonstrated that the C2 alkoxyl of the solvolysis products originated from the solvent, suggesting that these conversions may proceed through an S(N)1 mechanism with generation of a carbocation intermediate. The chemical structures of kallolide A derivatives 3-7and those of isokallolide A congeners 9-11 were established by detailed analysis of the spectral data.
Four diterpenes and a nor-diterpenoid, all of which possess unusual carbocyclic skeletons, were isolated from the hexane solubles of the West Indian gorgonian Pseudopterogorgia elisabethae. The structures and relative configurations of novel metabolites elisabethin D (2), elisabethin D acetate (3), 3-epi-elisabanolide (5), elisapterosin A (6), and elisapterosin B (7) were elucidated by interpretation of overall spectral data, which included 2D NMR correlation methods, IR, UV, and accurate mass measurements (HREI-MS and HRFAB-MS), chemical reactions, and X-ray diffraction analyses. The tetracyclic carbon skeleton of the elisapterosins is undescribed and constitutes a new class of C(20) rearranged diterpenes. Elisapterosin B displays strong in vitro anti-tuberculosis activity.
[structure: see text] Colombiasin A (1) was isolated from an extract of the West Indian gorgonian octocoral Pseudopterogorgia elisabethae that showed strong inhibitorial activity against Mycobacterium tuberculosis H37Rv. Structure elucidation by interpretation of 2D-NMR spectroscopic data, IR, UV, and accurate mass measurements (HREI-MS) revealed that colombiasin A belongs to a previously undescribed class of C20 rearranged diterpenes possessing an intricate tetracyclic framework.
Two diterpenes, a novel seco-furanocembranolide (3) and the highly oxygenated cembranolide bipinnatolide K (4), have been isolated from the West Indian gorgonian octocoral Pseudopterogorgia bipinnata. The chemical structures of these compounds were determined by 1D and 2D NMR spectroscopy in combination with IR, UV, and HRFABMS analyses.
[formula: see text] Our screening for marine natural products with anti-tuberculosis activity from the West Indian gorgonian coral Pseudopterogorgia elisabethae resulted in the isolation of two active diterpenoid alkaloids, pseudopteroxazole (1) and seco-pseudopteroxazole (2). Their structures were elucidated by NMR spectral analysis, including a variety of two-dimensional techniques. Compounds 1 and 2 are previously undescribed diterpenoids containing the uncommon benzoxazole moiety. Biological screening studies indicated that pseudopteroxazole (1) is a potent growth inhibitor of Mycobacterium tuberculosis H37Rv, while seco-pseudopteroxazole (2) shows moderate to strong inhibitorial activity.
[formula: see text] A chemical study of the hexane extracts of the Caribbean gorgonian Pseudopterogorgia bipinnata (Verrill) collected in San Andrés Island, Colombia, has led to the isolation of an unprecedented heptacyclic C40 bis-diterpenoid, bisgersolanolide (1). The structure of this novel secondary metabolite, which was established by spectroscopic studies that included 2D NMR correlation methods, IR, UV, and accurate mass measurements, was confirmed by synthesis.
A chemical study of the sea feather Pseudopterogorgia bipinnata from Colombia has produced four known metabolites, namely, kallolide A (1), bipinnatin A (2), bipinnatin C (3), and bipinnatin J (4), in addition to nine previously undescribed diterpenes possessing an uncommonly high level of oxygenation. One of them, bipinnapterolide A (5), is a new representative of the pseudopterane family of diterpenes possessing the rare 2,3-epoxy-1,4-dione moiety. The other metabolites, bipinnatins G-I (6-8) and bipinnatolides F-J (9-13), are highly oxygenated cembranolide diterpenes. Their chemical structures including relative stereochemistry were established by detailed analysis of the spectral data in addition to X-ray diffraction analysis and NMR spectral comparisons with known pseudopterane and cembranolide models.
A chemical study of the hexane extracts of the gorgonian octocoral Pseudopterogorgia elisabethae collected in San Andrés Island, Colombia, led to the isolation of two highly conjugated amphilectane-type diterpenes, compounds 1 and 2. Their structures were established by spectroscopic studies, which included 2D NMR correlation methods, IR, UV, and accurate mass measurements (HREIMS).
1. Phencyclidine (PCP) is an inhibitor of the nicotinic acetylcholine receptor (AChR) with characteristics of an open-channel blocker. The location of PCP binding site on the AChR molecule is unknown. 2. PCP inhibits the AChR from electric organ with a higher potency than muscle AChR. To find the molecular basis of this difference, we expressed the two native and six hybrid receptors, and two receptors containing mutated mouse gamma subunits in Xenopus laevis oocytes. The inhibition of ACh-induced current in these receptors by PCP was studied using whole-cell voltage-clamp. All hybrid receptors generated robust ACh-induced currents, while incomplete receptors (gamma-less or delta-less) did not. 3. PCP potency was higher on hybrids containing Torpedo beta and gamma subunits regardless of the alpha and delta subunit origin. A mouse gamma subunit containing the asparagine 6' to the serine mutation in the M2 segment conferred a high sensitivity to PCP. 4. These results support the conclusion that the amino acid residues at the position 6' of the M2 segments contribute to the PCP potency difference between Torpedo and mouse receptors. 5. Another noncompetitive inhibitor of the AChR, the cembranoid eupalmerin acetate (EUAC), also inhibited the electric organ receptor with a somewhat higher potency than muscle AChR. However, the IC50 values for EUAC inhibition of hybrid receptors did not follow the pattern observed for PCP. Therefore, these two inhibitors interact differently with the AChR molecule.