Marina Gordaliza

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.

Cytotoxic Terpene Quinones from Marine Sponges

The 1,4-benzoquinone moiety is a common structural feature in a large number of compounds that have received considerable attention owing to their broad spectrum of biological activities. The cytotoxic and antiproliferative properties of many natural sesquiterpene quinones and hydroquinones from sponges of the order Dictyoceratida, such as avarol, avarone, illimaquinone, nakijiquinone and bolinaquinone, offer promising opportunities for the development of new antitumor agents. The present review summarizes the structure and cytotoxicity of natural terpenequinones/hydroquinones and their bioactive analogues and derivatives.

Sesquiterpenoids and phenolics of pulicaria paludosa

Abstract Thirteen sesquiterpenoids of the skeletal types caryophyllane, cadinane, oplopane, eudesmane, allo-aromadendrane and 4-epi-guaiane, were isolated from Pulicaria paludosa. Their structures were established mainly by NMR techniques and chemical transformations. Four of them are new natural products. Three flavonoids and some simple phenolic derivatives were also isolated.

The distribution of lignanoids in the order coniferae

Lignan distribution in the Coniferae order, which includes six families, has been reviewed from 1967 to 1994. The occurrence of lignanoids in five of the six families of this order has been reported and the predominant lignan type is different for each one.

Preparation and cytotoxicity of podophyllotoxin derivatives lacking the lactone ring

Abstract Several cyclolignans lacking of the lactone moiety can easily be prepared from naturally occurring lignans such as podophyllotoxin and deoxypodophyllotoxin by simple chemical transformations. Their cytotoxicity has been studied in four tumoral cell lines. Most of the compounds show similar effects in all the neoplastic systems tested, except the aldehyde 9 (methyl 9-deoxy-9-oxo-α-apopicropodophyllate) and the hydrazones 16 and 17 which show a highly selective cytotoxicity towards HT-29 human colon carcinoma. Additionally, several molecular modeling studies have been done with aldehyde 9 and the corresponding saturated aldehyde 13 in comparison with podophyllotoxin.

Lignans from Juniperus sabina

Abstract Four new natural products, β-peltatin-B methyl ether, podorhizol acetate, 2′-methoxyepipicropodophyllotoxin and 2′-methoxypicropodophyllotoxin, were isolated from the lignan fraction of a n -hexane extract from the leaves of Juniperus sabina , along with picropodophyllotoxone, epipodophyllotoxin, (+)-dihydrosesamin, podorhizol, anhydropodorhizol, epipicropodophyllotoxin and 2′-methoxypodophyllotoxin.

Acetylated lignans from Juniperus sabina

Abstract Two new natural products, the acetates of epipodophyllotoxin and epipicropodophyllotoxin, were isolated from the lignan fraction of a n -hexane extract of the leaves of Juniperus sabina , along with deoxypodophyllotoxin, deoxipicropodophyllotoxin, (−)-deoxypodorhizon, β-peltatin A methyl ether and picropodophyllotoxin.

In vivo immunosuppressive activity of some cyclolignans

Abstract Several podophyllotoxin-related cyclolignans, either lacking the lactone ring or the methylenedioxy grouping, have been prepared and evaluated for their immunosuppressive (IMS) activity in the mouse allogeneic MLR in vitro test and in the in vivo techniques Graft vs Host Reaction (GVHR) and Skin Grafting (SG). The results obtained show that three cyclolignans fairly prevent splenomegaly in comparison with control animals and also promoted tolerance to grafting, being the first time that the in vivo IMS activity of cyclolignas is reported.

Cytotoxic cyclolignans related to podophyllotoxin

The cyclolignan 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, cyclolignans have been the objective of numerous studies focused to prepare better and safer anticancer drugs. Several cyclolignans related to podophyllotoxin have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28); some of them have antiviral and immunosuppressive activities.

Terpenyl-Purines from the Sea

Agelasines, asmarines and related compounds are natural products with a hybrid terpene-purine structure isolated from numerous genera of sponges (Agela sp., Raspailia sp.). Some agelasine analogs and related structures have displayed high general toxicity towards protozoa, and have exhibited broad-spectrum antimicrobial activity against a variety of species, including Mycobacterium tuberculosis, and also an important cytotoxic activity against several cancer cell lines, including multidrug-resistant ones. Of particular interest in this context are the asmarines (tetrahydro[1,4]diazepino[1,2,3-g,h]purines), which have shown potent antiproliferative activity against several types of human cancer cell lines. This review summarizes the sources of isolation, chemistry and bioactivity of marine alkylpurines and their bioactive derivatives.