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Md Ahad Ali,
Robert B Bates,
Zackary D Crane,
Christopher W Dicus,
Michelle R Gramme,
Ernest Hamel,
Jacob Marcischak,
David S Martinez,
Kelly J McClure,
Pichaya Nakkiew,
George R Pettit, Chad C Stessman,
Bilal A Sufi,
Gayle V Yarick
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ABSTRACT: Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.
Bioorganic & Medicinal Chemistry 08/2005; 13(13):4138-52. · 2.92 Impact Factor
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ABSTRACT: A Fijian collection of the calcareous sponge Leucetta sp. was investigated and yielded four new imidazole alkaloids. One compound, (+)-calcaridine A (6), is unique in its overall structure and consists of a geminally substituted 2-aminoimidazolidinone. An additional compound, (-)-spirocalcaridine A (7), is distinctive in its hexahydrocyclopentamidazol-2-ylidenamine spiro-linked to a cyclohexenone. A third compound, (-)-spirocalcaridine B (8), is the OCH(3) analogue of 7. These compounds have unprecedented skeletons and functionality and are the first nonorganometalic chiral aminoimidazoles isolated from calcareous sponges. The two issues discussed here include the challenges associated with the structure elucidations of 6 and 7 and the relationships to previously encountered Leucetta metabolites.
Journal of Natural Products 08/2003; 66(7):939-42. · 3.13 Impact Factor
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ABSTRACT: To sharpen the search for new lipoxygenase inhibitors, we designed a screen to probe for both potency and selectivity. The assay utilized 12-human (12-HLO), 15-human (15-HLO), and 15-soybean (15-SLO) lipoxygenases. The IC(50) value data obtained provided new insights about structure-activity relationships (SAR) for redox and nonredox inhibitors. All of the compounds tested were isolated from sponges and consisted of a novel terpenoid, hyrtenone A (1), and 12 known terpenoids. Potent compounds were defined as those having IC(50) values < 1 microM, and selectivity was assessed from the three possible IC(50) value ratios. One of the four terpenoid redox inhibitors studied, puupehenone (2), was equivalent to or better in potency than the well-known redox inhibitor nordihydroguarierate acid (NDGA, 14). However, none of the terpene redox inhibitors exhibited a selectivity ratio on a par with that of 14. Several potent nonredox inhibitors were identified, and one, dimethoxypuupehenol (5), exhibited notable selectivity. The structural elucidation of 1 and the SAR results for 13 natural products are reported. This study suggests that sponge-derived terpenes are a promising source for new lipoxygenase inhibitors.
Journal of Natural Products 02/2003; 66(2):230-5. · 3.13 Impact Factor
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ABSTRACT: The sesterterpene constituents of two Indo-Pacific sponges were investigated and rapidly characterized using aggressive dereplication methods along with gradient 1D NMR techniques. Lendenfeldia frondosa yielded three sesterterpenes: 12beta,16beta,22-trihydroxy-24alpha-methylscalar-25beta,24alpha-olide (1), the 24 epimer of a known compound; 12beta,22-dihydroxy-24-methylscalar-17-en-24,25-olide (2), a known compound; and 22-hydroxy-24-methylsedn-16-en-24-one-12beta,25beta-olide (3), a new compound. A Hyrtios sp. sponge yielded known 12alpha-acetoxy-16beta-hydroxyscalarolbutenolide (5).
Journal of Natural Products 09/2002; 65(8):1183-6. · 3.13 Impact Factor
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ABSTRACT: Three triterpene saponins named Styrax-saponin A-C (1-3) were found in pericarps of Styrax officinalis together with the deacylsaponin (4). Structural determinations were achieved using 1D-, 2D-NMR and mass spectrometry.
Fitoterapia 08/2002; 73(4):320-6. · 1.85 Impact Factor
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ABSTRACT: The two cyclic hemiacetals of 30-hydroxyfriedelan-3-on-28-al (1R and 1S) were found in an undescribed Salacia species from Costa Rica and characterized by spectral methods.
12/1998;
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Robert B. Bates,
Kennard G. Brusoe,
Jennifer J. Burns,
Sriyani Caldera,
Wei Cui,
Sanjeev Gangwar,
Michelle R. Gramme,
Kelly J. McClure,
Gregory P. Rouen,
Heiko Schadow, Chad C. Stessman,
Stuart R. Taylor,
Vicky H. Vu,
Gayle V. Yarick,
Jianxing Zhang,
George R. Pettit,
Roger Bontems
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ABSTRACT: The first synthesis of dolastatin 11, a potent antineoplastic agent from the sea hare Dolabella auricularia, confirmed the proposed structure and established the last configuration in this natural product and in dolastatin 12, majusculamide C, and 57-normajusculamide C.
03/1997;
