Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis.

We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.

Inhibition of DNA topoisomerase II by azaelliptitoxins functionalized in the variable substituent domain.

A series of novel C11-substituted derivatives of azaelliptitoxin (azatoxin) have been synthesized and tested for their inhibitory activity against human DNA topoisomerase II. Incorporation of a C11 polyamine or amine resulted in an increase in the intercalation properties of the drug and a decrease of topoisomerase II activity. The structure-activity relationship (SAR) profile of the nonintercalating C11 anilino azatoxin class follows the SAR of the (anilino)acridine family. 11-(4-Cyanoanilino)azatoxin (14) was found to be the most active analog in this series, exhibiting approximately 10-fold higher activity than azatoxin 12 and etoposide.

Cleavable complex formation in Leishmania chagasi treated with anilinoacridines.

Anilinoacridines have recently been found to possess antiparasitic activity toward Leishmania, Trypanosoma, and Plasmodium species. These compounds have been examined for their ability to generate cleavable complex, the protein-associated DNA lesion characteristic of topoisomerase II involvement, in intact L. chagasi promastigotes. At cytotoxic concentrations, anilinoacridine compounds give cleavable complex in a whole cell assay which suggests that the drugs affect a nuclear topoisomerase II in the parasite. Linearization of kinetoplast DNA minicircles also occurs in parasites treated with anilinoacridines at similar concentrations. Exonuclease digestions reveal that the linearized minicircles are blocked at the 5' end but not at the 3' end, further implicating a kinetoplast topoisomerase II in the cleavage process. Interestingly, cytotoxic alkylaminoacridines did not stimulate the production of cleaved DNA in the same experiments. DNA binding experiments showed no apparent correlation between the affinity of the compounds for DNA and antileishmanial activity. Although multiple cytotoxic mechanisms are likely at work, these experiments suggest that topoisomerase II enzyme(s) are affected by antileishmanial anilinoacridines.