Paolo Lombardi

New developments in antitumor anthracyclines

Doxorubicin is a major anticancer agent introduced to extended clinical use in the early 1970s. The fulfillment of a wide program of analogue synthesis led to the development of the better tolerated epirubicin and of a highly potent antileukemic drug, idarubicin. In recent years, on the basis of the available information on the molecular requirements for action, a new synthetic program, coupled with target-oriented pharmacological experiments, was carried out. Various interesting derivatives, namely, the 8- and 10-fluoro compounds and the disaccharides, were obtained. The latter compounds exhibited a strong dependence of biological activity on the orientation (axial vs. equatorial) of the second sugar moiety, daunosamine. A member of this group, namely, 7-O-(4-O-alpha-L-daunosaminyl-2-deoxy-alpha-L-fucosyl)-4-demetho xy-adriamycinone, is presently undergoing clinical trials as a third generation antitumor anthracycline.

Synthesis of aryl 2-benzofuranyl and aryl 2-indolyl carbinols of high enantiomeric purity via palladium-catalyzed heteroannulation of chiral arylpropargylic alcohols

Abstract 2-Iodophenol and 2-iodo-N-mesylaniline have been reacted with α-arylpropargylic alcohols of high enantiomeric purity under transition-metal catalysis leading to aryl 2-benzofuranyl and aryl 2-indolyl carbinols in good yield and high enantiomeric excess, thus constituting the first enantiospecific synthesis of these important classes of compounds.

New anthracycline disaccharides. Synthesis of L-daunosaminyl-α(1 →4)-2-deoxy-L-rhamnosyl and of L-daunosaminyl-α(1 →4)-2-deoxy-L-fucosyl daunorubicin analogues

The synthesis of the new disaccharide anthracyclines 20, 21, 24 and 25, where the daunosamine moiety is separated from the aglycone by either a rhamnose or a fucose residue, performed following a convergent procedure, gives insight into the configurational requirement of the first sugar residue and opens the way to a new class of antitumour anthracyclines.

Binding of Epstein-Barr virus nuclear antigen 1 to DNA : inhibition by distamycin and two novel distamycin analogues

Modulation of the interaction between cellular or viral transcription factors and target DNA sequences may represent a potential experimental strategy to control proliferation of neoplastic cells as well as virus DNA replication. Distamycin represents a likely candidate to mediate such modulation by pharmacological means. In order to obtain more detailed information on structure-activity relationships of these compounds, we have analysed the effects of distamycin and two distamycin analogues on the binding of a recombinant protein, the Epstein-Barr virus nuclear antigen 1 (EBNA-1) to its target sequence of Epstein-Barr virus, containing the 12 bp palindromic consensus TAGCATATGCTA. The sequence selectivity in the binding of distamycin to DNA was evaluated by footprinting experiments, while the effects of distamycins on DNA-protein interactions was analysed by means of electrophoretic mobility shift assay. The data presented in this paper suggest that distamycin and its analogues differentially inhibit the interaction between DNA-binding proteins and target DNA sequences.

Antimalarial activity of synthetic analogues of distamycin.

Malaria, one of the most serious diseases transmitted by arthropods, is largely present in tropical and even temperate zones in endemic or epidemic form. More than 40% of the worlds population lives in areas at risk for exposure, and the World Health Organization reports that approximately 300 million people are affected by the infection (mostly caused by the species Plasmodium falciparum), with 1-2 million deaths per year. These data, and the fact that malaria is becoming increasingly refractory to treatment through resistance of the parasite to antimalarial agents currently in use, e.g., chloroquine, emphasize the need to develop new drugs. The well-known antiparasitic activity of oligopyrrolamidine natural products, such as distamycin and netropsin, suggested the antimalarial evaluation of related compounds obtained by new chemical modifications. Besides possessing antiviral and antitumoural properties, distamycin exhibits interesting in vitro activity against P. falciparum. Unfortunately, the high toxicity associated with this product precludes its development as a drug. However, some synthetic analogues of distamycin proved to be highly active against chloroquine-sensitive and -resistant strains of P. falciparum, besides showing low toxicity in vitro.

Determination of absolute configuration of the derivative from 2-[4-(1-oxo-2-isoindolinyl)-phenyl]-propionic acid and R-(+)-1-phenylethylamine by 1H-NMR spectroscopy; use of shift reagent with diastereoisomeric amides

The assignment of the S-(+), R-(−) absolute configuration of Indoprofene, an analgesic and anti-inflammatory drug, has been made via an NMR configurational correlation of diastereoisomeric phenylethylamides with the aid of Eu(fod)3.

Distamycin analogues with improved sequence-specific DNA binding activities

In the present study we have investigated the effect of unprecedented chemical modifications introduced in the distamycin molecule, with the aim of assessing their ability to interfere with sequence-specific DNA-protein interactions in vitro. By using an electrophoretic mobility shift assay, we have been able to identify novel distamycin analogues with improved displacing abilities on the binding of octamer nuclear factors to their target DNA sequence. While variations in the number of pyrrole rings and/or reversion of an internal amide bond result in distamycin-like compounds with identical or very similar properties, the reversion of the formamido into a carboxyamido group or its replacement with the charged formimidoyl moiety significantly improves the ability of the resulting novel distamycin derivatives to compete with OCT-1 (octamer 1 nuclear factor) for its target DNA sequence. Tissue-specific octamer-dependent in vitro transcription is similarly affected by these chemical modifications, suggesting that the ability of distamycins to bind octamer sequences has a direct influence on the functional state of octamer-containing promoters. These data represent an initial, successful attempt to rationalize the design of DNA binding drugs, using distamycins as a model.

Conformational analysis of 4-demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-l-lyxo-hexopyranosyl)- α-l-lyxo-hexopyranosyl]adriamicinone, the first doxorubicin disaccharide analogue to be reported

Abstract The solution conformation of 4-demethoxy-7- O -[2,6-dideoxy-4- O -(2,3,6-trideoxy-3-amino- α -l-lyxo-hexopyranosyl)- α -l-lyxo- hexopyranosyl]adriamicinone, the first doxorubicin disaccharide analogue to be reported, has been analysed using nuclear magnetic resonance data and molecular mechanics calculations. In order to consider the possibility of conformational averaging we have used the NAMFIS programme (NMR analysis of molecular flexibility in solution), that considers all reasonable structures and classifies them with regard to their relative capability of reproducing the experimental data. In this way we have determined the conformation of ring A of the aglycone of the sugar moieties and the preferred orientation around the glycosidic linkages.

N-formimidoyl analogues of distamycin

Novel N-formimidoyl analogues of distamycin, bearing a second positive charge (3–5) or a single positive charge (6) at the N-terminus, were synthesised and assayed for their DNA affinity and anti-herpes activity.

4-tetrahydropyranthioazetidinyl phosphoranes: Versatile intermediates in the synthesis of 2-penems

Abstract The total synthesis of four racemic trans -6-ethyl-2-penems has been developed using the 4-tetrahydropyranthioazetidinyl phosphorane 10 as a common precursor.