Maria Angeles Castro

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.

Synthesis, cytotoxicity and antiplasmodial activity of novel ent-kaurane derivatives

This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs.

Synthesis and biological evaluation of cytotoxic 6(7)-alkyl-2-hydroxy-1,4-naphthoquinones

Various Diels Alder cycloaddition conditions have been used to optimise the preparation of cytotoxic 6‐alkyl‐1, 4‐naphthoquinones, which were subsequently transformed into 6(7)‐alkyl‐2‐hydroxy‐1, 4‐naphthoquinones. The compounds thus prepared were evaluated for their cytotoxic activity against several neoplastic cultured cell lines and some of them showed IC50 values below the μM level.

Neo-clerodane diterpenoids from roots of Linaria saxatilis var. Glutinosa

Abstract Two new and four known neo-clerodane diterpenoids were isolated from an n-hexane extract of the roots of Linaria saxatilis var. saxatilis. The structures of the new compounds were established from the spectral data as 15,16-diacetoxy-15,16-epoxy-neo-cleroda-3,12Z-diene, and 15,16-diacetoxy-12,13-15,16-diepoxy-14-hydroxy-neo-clerod-3-ene.

iso-Kaurenoic acid from Wedelia paludosa D.C.

A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.

Synthesis and cytotoxic evaluation of new terpenylpurines

Several new terpenylpurine derivatives were prepared through alkylation of different purines with halogenated reagents derived from natural terpenoids, commercially available or isolated from cones of C. sempervirens L. and further transformed into appropriate alkylated agents. Alkylation of the purines gave mixtures of 9- and 7-alkylpurines, being the 9-alkylpurines the major regioisomers. The presence of the terpenyl residue induced cytotoxicity on simple purines and, in general, that activity improved as the substituent was larger. The 7-diterpenyl-6-chloropurine E-21b was the most cytotoxic in the series and it can be considered an analogue of the marine natural compounds agelasines and agelasimines, which were taken as models for this work.

Synthesis and evaluation as antitumor agents of 1,4-naphthohydroquinone derivatives conjugated with amino acids and purines.

We report on the synthesis of two series of 1,4‐naphthohydroquinone derivatives conjugated with amino acids (Gly, Ala, Phe, and Glu) and with substituted purines linked by an aliphatic chain. The compounds were obtained through Diels–Alder cycloaddition between myrcene and 1,4‐benzoquinone and evaluated in vitro for their cytotoxicity (GI50) against cultured human cancer cells of A‐549 lung carcinoma, HT‐29 colon adenocarcinoma, and MCF‐7 breast carcinoma. The GI50 values found for some hydroquinone–amino acid and hydroquinone–purine hybrids against MCF‐7 are in an activity range comparable to that of the reference drug doxorubicin.

Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum

Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian – mouse non-infected splenocytes and liver HepG2 cells – in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.