Tawnya C. McKee

The guttiferones, HIV-inhibitory benzophenones from Symphonia globulifera, Garcinia livingstonei, Garcinia ovalifolia and Clusia rosea

Abstract Extracts from species of the tropical plant genera Symphonia , Garcinia and Clusia (Guttiferae) have yielded a series of new polyisoprenylated benzophenone derivatives named guttiferones A–E (1–5). Structural assignments were based on detailed spectral analysis. These compounds inhibit the cytophatic effects of in vitro HIV infection.

Anti-HIV Cyclotides

The cyclotides are a recently discovered, structurally unique family of bioactive plant peptides. Their discovery spawned a series of structural analyses, synthetic efforts, and studies to define the biosynthesis and biological properties of these novel peptide metabolites. Cyclotides have a head-to-tail cyclized amino acid backbone and a conserved cystine knot motif that provides an extremely stable structural framework. They all share a common global fold and are highly resistant to denaturation and to cleavage by proteolytic enzymes. However, these macrocyclic peptides are quite permissive to amino acid substitutions or additions in several peripheral loop regions, since changes in these loops do not alter the core cyclotide structure. These features make cyclotides attractive templates for incorporating desired amino acid sequences and then delivering these peptide sequences in a well defined, highly stable framework. Cyclotides likely function in a defensive role in the source plants since they exhibit a broad spectrum of antimicrobial activity and are detrimental to the growth and survival of herbivorous insects. Cyclotides are gene-encoded polypeptides that are cleaved from larger precursor proteins and then cyclized. This review summarizes research done on a subset of cyclotides that were discovered due to their HIV inhibitory properties. It details the isolation and characterization of these compounds and describes this work in the context of our current state of knowledge of the entire cyclotide family.

Novel marine and microbial natural product inhibitors of vacuolar ATPase.

Vacuolar-ATPase (V-ATPase) has been proposed as a drug target in osteoporosis due to its involvement in bone resorption, and as a target in cancer due to potential involvement in tumor invasion and metastasis. The classical selective inhibitors of V-ATPase are microbial macrolides of the bafilomycin and concanamycin class. These inhibitors have proven to be too toxic for therapeutic use, however recent structure-activity studies on bafilomycins, and the isolation of novel macrolide structures from marine sources, have provided new avenues for development of potentially less toxic V-ATPase inhibitors. The novel salicylihalamide and lobatamide series of compounds were predicted to share a common mechanism of action based on the patterns of cytotoxicity produced in the NCI 60-cell cancer screen. They have subsequently been shown to selectively interact with mammalian V-ATPases, but not with fungal V-ATPases. With the recent achievement of total syntheses of salicylihalamide, lobatamide, and related compounds, the elaboration of congeners with specificity for particular enzyme isoforms may provide drug candidates which are less toxic. This review summarizes recent advances in V-ATPase inhibition and the prospects for further progress.

Coscinamides A, B and C, three new bis indole alkaloids from the marine sponge Coscinoderma sp.

Abstract Three novel bis indole alkaloids, coscinamides A–C have been isolated from an extract of the marine sponge Coscinoderma sp., and their structures determined on the basis of spectral data. These compounds contain an unusual α-keto enamide functionality and are the first reported alkaloids from this genus.

Suberosenone, a new cytotoxin from Subergorgia suberosa☆

The organic extract of the gorgonian Subergorgia suberosa was found to contain a novel cytotoxic sesquiterpene, suberosenone (1), as well as two known piscicidal sesquiterpenes, buddledins C and D. The structure of 1 was defined by spectral methods, including 1D and 2D NMR experiments. Suberosenone, the first quadrone-class sesquiterpene from the marine biosphere, exhibited relatively potent cytotoxicity to solid tumor lines in comparison to leukemia lines in the NCIs 60 cell line in vitro screen.

Diplamine, a cytotoxic polyaromatic alkaloid from the tunicate diplosoma sp.

Abstract A novel cytotoxic alkaloid, diplamine ( 3 ) was isolated from the tunicate Diplosoma sp. The structure was established by interpretation of spectral data and chemical analysis.

HIV-inhibitory coumarins from latex of the tropical rainforest tree Calophyllum teysmannii var. inophylloide

Abstract In an effort to identity an adequate and sustainable natural source of the recently decribed anti-HIV drug development candidate calanolide A, we undertook chemical and biological studies of the latex exuded from trees of the genus Calophyllum . Although we found that calanolide A was not present in latex from the original source species, C. lanigerum var. austrocoriaceum , we did observe that a related coumarin, costatolide, was abundant in latex of C. teysmanii var. inophylloide . Costatolide is currently being evaluated as a possible alternative to calanolide A for drug development.

Clerodane Diterpenes from Casearia arguta That Act As Synergistic TRAIL Sensitizers

Casearia arguta was investigated as part of the ongoing search for synergistic TRAIL (tumor necrosis factor-α-related apoptosis-inducing ligand) sensitizers. As a result of this study, argutins A-H, eight new highly oxygenated clerodane diterpenes, were isolated from the plant Casearia arguta collected in Guatemala. The modified Mosher ester method was utilized to establish the absolute configuration of argutins A and F. Each of the argutins showed varying levels of synergy with TRAIL. Argutin B showed the highest TRAIL sensitization; the synergistic effect of argutin B and TRAIL together was 3-fold greater than argutin B alone.

Ibisterol sulfate, a novel HIV-inhibitory sulfated sterol from the deep water sponge Topsentia sp.

Abstract The novel sulfated sterol ibisterol sulfate ( 1 ) was isolated from the deep water Caribbean sponge Topsentia sp. The combination of both a Δ 9(11) olefin and a methyl group at C-14 has not previously been reported in sponge sterols.

Resolution and comparative anti-HIV evaluation of the enantiomers of calanolides A and B

Methods for the chiral resolution of (+)-calanolide A and (-)-calanolide A from synthetic (:i:)- calanolide A, and of (+)-ealanolide B and (-)-calanolide B (costatolide) from a scalemic mixture isolated from C. lanigerium, have been developed. Calanolide A was originally isolated as the pure (+) enantiomer from C. lanigerum, but now is also shown to occur as a scalemic mixture in latex of C. teysmannii. Interestingly, (+)-calanolide A and (-)-¢alanolide B are potent HIV-1 inhibitors, while (-)-¢.alanolide A and (+)-calanolide B are inactive against the virus. The novel coumarin derivative (+)-calanolide A (1) was first isolated and identified from leaves and twigs of the Malaysian rainforest tree Calophyllum lanigerum vat. austrocoriaceum by our laboratory. 2 Its HIV-inhibitory activity was subsequently characterized as representative of a new class of non-nucleoside HIV-I specific reverse transcriptase inlfibitors) As such, calanolide A has been selected by the NCI Division of Cancer Treatments Decision Network Committee for preclinical drug development. As with many natural products, 4 the procurement of adequate supplies of (+)-calanolide A for detailed biological evaluation has proved to be quite challenging. The compound is a minor component of the leaves (_~1 mg/g extract) and is even less concentrated or completely undetectable in the more abundant bark and latex extracts. 5 Recently, scientists at SmithKline Beecham reported a synthesis of racemic calanolide A. 6 Since a chiral synthesis was not yet available, and because a comparison of the bioactivity of (+)-calanolide A and (-)-¢.alanolide A was of interest, we initially pursued a chiral separation approach with synthetic (+)- calanolide A. Herein we report a simple and efficient semi-preparative separation of the enantiomers of calanolide A and their preliminary biological evaluation. We also describe the results of extension of this method to the resolution and biological evaluation of the enantiomers of the related 2 calanolide B.