J. M. Miguel Del Corral

Antitumor properties of podophyllotoxin and related compounds.

The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.

Terpenoids from leaves of Juniperus thurifera

Abstract Nineteen diterpenoids of the labdane, pimarane and abietane skeletons and four known sesquiterpenoids were isolated from Juniperus thurifera leaves. Thirteen of these diterpenoids are described for the first time as natural products. Their structures were elucidated principally by NMR techniques and chemical transformations.

Asteriscanolide: a sesquiterpene lactone with a new natural skeleton

Abstract A sesquiterpene lactone was isolated from the hexane extract of Asteriscus aquaticus . Its constitution and stereochemistry were determined by spectroscopic techniques, principally two-dimensional NMR correlations (COSY, HCCORR, RELAY) and with the interpretation of certain chemical transformations. The results were confirmed by X-ray diffraction and the name asteriscane is proposed for the new natural skeleton.

Aquatolide. A new type of humulane-related sesquiterpene lactone

Abstract A new sesquiterpene lactone called aquatolide was isolated from the hexane extract of Asteriscus aquaticus . Its constitution and stereochemistry were deduced from spectroscopic data, mainly homonuclear and heteronuclear two-dimensional NMR correlations.

Asteriscunolides A, B, C and D, the first humulanolides; Two pairs of conformationally stable stereoisomers

Abstract Following a preliminary comunication on Asteriscunolide A (the first reported natural humulanolide), three more configurationally and/or conformationally isomeric Asteriscunolides ( B, C and D ) from the same plant ( Asteriscus aquaticus L.) are described. The absolute configurations and the stable conformations of all four Asteriscunolides are established by an array of spectroscopic methods (CD, 1H and 13C NMR) without resorting to X ray analysis.

Eudesmane glycosides from Carthamus lanatus

Abstract Two new eudesmane glycosides, intermedeol β- d -fucopyranoside and its 2′ α-methylbutyrate, were isolated from the hexane extract of Carthamus lanatus and their structures established by spectral and chemical means.

Asteriscunolide A: Humulanolide from asteriscus aquaticus

A number of humulanolides and other sesquiterpene lactones have been isolated from Asteriscus aquaticus (L). The structure, absolute stereochemistry and conformation of the major component, asteriscunolide A, have been determined.

Thuriferic acid. A novel lignan type from juniperus thurifera l

Abstract The isolation and structural determination of a novel type of lignan, thuriferic acid, obtained from the hexane extract of the leaves of Juniperus thurifera L (Cupressaceae) are described. Its structure was confirmed by synthesis and the signals of its 1H and 13C NMR spectra were assigned unequivocally by two-dimensional techniques.

Chemoinduction of cytotoxic selectivity in Podophyllotoxin-related lignans

Lignans are widely distributed in the plant kingdom, and display a variety of biological activities which have attracted the attention of the scientific community for decades. Several representative compounds of the cyclolignan class, such as podophyllotoxin and its semisynthetic derivative, etoposide, are currently used for the clinical treatment of warts and malign neoplasms. Other cyclolignans are involved in antineoplastic and antiarthritic clinical trials. Numerous podophyllotoxin-related compounds have been prepared through modification of nearly all the positions on the cyclolignan skeleton in the search of new, more selective and less toxic anticancer drugs. Our group has been interested in the chemoinduction of drug selectivity for several years, and we have designed and prepared new podophyllotoxin derivatives by modification mainly on the C and D-rings of the podophyllotoxin skeleton. Those derivatives, bearing an electrophilic functionality at C-9, have shown, both in vitro and in vivo, a high degree of selectivity against colon carcinoma, and less cytotoxicity for other neoplastic systems and normal kidney fibroblasts. The main structural modifications found in the literature for the podophyllotoxin skeleton in the past decade, including those from our research group, are presented in this article.

Inhibition of human sPLA2 and 5-lipoxygenase activities by two neo-clerodane diterpenoids.

The inhibitory effect of two neo-clerodane diterpenoids, E-isolinaridial (EI) and its methylketone derivative (EIM), isolated from Linaria saxatilis var. glutinosa, on PLA2 and other enzyme activities involved in the inflammatory process was studied. Both compounds inhibited human synovial sPLA2 in a concentration-dependent manner with IC50 values of 0.20 and 0.49 microM, respectively, similar to scalaradial. Besides, these compounds decreased the cell-free 5-lipoxygenase activity and A23187-induced neutrophil LTB4 biosynthesis. Another function of human neutrophils, such as receptor-mediated degranulation, was also significantly reduced. In contrast, none of the compounds affected superoxide generation in leukocytes, or cyclooxygenase-1, cyclooxygenase-2 and inducible nitric oxide synthase activities in cell-free assays.