Regioselective synthesis and biological profiling of butyric and phenylalkylcarboxylic esters derivated from D-mannose and xylitol: influence of alkyl chain length on acute toxicity

Regiospecific synthesis of 12 novel il-butyric and phenylalkylcarboxylic mo noesters of mannose and xylitol was achieved. The strategy adopted, avoided a tedious intramolecular transesterification step, previously described fo r the synthesis of analogous compounds and permitted the facile synthesis o f a new generation of stable derivatives. The general tolerance of the drug s has been assayed after intravenous administration of a bolus dose into mi ce, Monobutyric esters showed a low toxicity commensurate with the requirem ents for future development. A relationship was observed between chain leng th and toxicity. In contrast, phenylacetic, 3-phenylpropionic and 4-phenylb utyric esters were found to be toxic. Phenylbutyric esters induced marked a nd specific neuromuscular damage. Preliminary biological investigations of the new series of monobutyric esters showed them to retain the benificial b iological properties of butyric acid whilst remaining relatively non toxic. They induced an inhibition of in vitro proliferation of 10 human cases of de novo acute myeloid leukemia (AML) primary cultures and AML established c ell lines. AML blasts growth appeared to be blocked and cell differentiatio n was established. Transcription and expression of maturation markers and f inally apoptosis were observed. Moreover, human gamma-chain hemoglobin (HbF ) synthesis in erythroleukemia cells was stimulated by monobutyric esters. Mannose and xylitol butyric derivatives would appear to have exciting poten tial in treatment of beta-Hemoglobinopathies, sickle cell anemia and cancer . (C) 1998 Elsevier Science B.V. All rights reserved.