4-hydroxy-25-desoxyneorollinicin and Colonic-Neoplasms

A synthesis of four Annonaceous acetogenins, asiminocin, asimicin, asimin, and bullanin, by a modular approach from seven fundamental subunits, A-G, is described. The approach employs a central core aldehyde segment, C, to which are appended an aliphatic terminus, A or B, a spacer subunit, D or E, and a butenolide terminus, F or G. Coupling of the A, B, D, and E segments to the core aldehyde unit is effected by highly diastereoselective additions of enantiopure allylic indium or tin reagents. The butenolide termini are attached to the ACD, BCE, or BCD intermediates by means of a Sonogashira coupling. The design of the core, spacer, and termini subunits is such that any of the C30, C10, or C4 natural acetogenins or stereoisomers thereof could be prepared. IC50 values for the four aforementioned acetogenins against H-116 human colon cancer cells were found to be in the 10(-3) to 10(-4) microM range. The IC90 activities were ca. 10(-3) microM for asimicin and asimin but only 0.1-1 microM for bullanin and asiminocin.

Topics: Antineoplastic Agents, Phytogenic; Catalysis; Colonic Neoplasms; Drug Screening Assays, Antitumor; Furans; Humans; Indicators and Reagents; Lactones; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Stereoisomerism; Tumor Cells, Cultured; X-Ray Diffraction

Annonaceous acetogenins (ACG) are a large family of natural products that have been described as the most potent in vitro inhibitors of the mitochondrial respiratory chain Complex I. During the last two decades a large number of related structures have been discovered, increasing the number of members of this family. The large diversity of structural moieties and the general trends observed for inhibiting both growth of tumor cell lines and mitochondrial respiratory chain activity have resulted in the classification of these compounds into several structural groups according to their potency. Among them, the adjacent bis-tetrahydrofuranic acetogenins (bis-THF ACG) with a threo/cis/threo/cis/erythro relative configuration, have been described as the most potent subgroup, the prototypical member of which, rolliniastatin-1, was originally isolated from Rollinia membaranacea seeds. In this report we describe the different structure-activity relationships (SAR) observed for some natural ACG and semisynthetic derivatives as growth inhibitors of human tumor breast, lung, liver, and colon cell lines. All the compounds assayed showed potencies in the micromolar range. Trends observed in the cytotoxicity assay have been compared with previous data reported for these compounds as inhibitors of mitochondrial respiratory chain.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Drug Design; Electron Transport; Female; Furans; Humans; Liver Neoplasms; Lung Neoplasms; Mitochondria; Structure-Activity Relationship; Therapeutic Equivalency

The (4R)-hydroxylated analogues of annonaceous acetogenin mimicking compound 2 were designed and synthesized structurally on the basis of the naturally occurring annonaceous acetogenin bullatacin, which was discovered as a typical member of the novel family of polyketides with potent cytotoxicity, antitumoral, and other biological activities. The preliminary screenings show that the IC(50) values of 2 were 1.6 x 10(-3) and 8 x 10(-2) microg/mL against HT-29 and HCT-8, respectively. A remarkable enhancement effect was observed by the activity comparison of 1c and its (4R)-hydroxylated analogue 2.

Topics: Annonaceae; Antineoplastic Agents, Phytogenic; Cells, Cultured; Colonic Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Furans; Humans; Inhibitory Concentration 50; Intestines; Molecular Mimicry; Molecular Structure; Stereoisomerism; Tumor Cells, Cultured