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 n-butyric and phenylalkylcarboxylic monoesters of mannose and xylitol was achieved. The strategy adopted, avoided a tedious intramolecular transesterification step, previously described for the synthesis of analogous compounds and permitted the facile synthesis of a new generation of stable derivatives. The general tolerance of the drugs has been assayed after intravenous administration of a bolus dose into mice. Monobutyric esters showed a low toxicity commensurate with the requirements for future development. A relationship was observed between chain length and toxicity. In contrast, phenylacetic, 3-phenylpropionic and 4-phenylbutyric esters were found to be toxic. Phenylbutyric esters induced marked and specific neuromuscular damage. Preliminary biological investigations of the new series of monobutyric esters showed them to retain the benificial biological 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 cell lines. AML blasts growth appeared to be blocked and cell differentiation was established. Transcription and expression of maturation markers and finally 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 potential in treatment of beta-Hemoglobinopathies, sickle cell anemia and cancer.
Pouillart
P
P
Laboratoire de Chimie Organique and Cinétique, UFR des Sciences, Université de Picardie Jules Verne 80039, Amiens, France.
Douillet
O
O
Scappini
B
B
Gozzini
A
A
Santini
V
V
Grossi
A
A
Pagliai
G
G
Strippoli
P
P
Rigacci
L
L
Ronco
G
G
Villa
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000138:chemical synthesis / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives / Q000633:toxicity*; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014993:Xylitol / Q000031:analogs & derivatives / Q000633:toxicity*
D000970:Antineoplastic Agents; D002087:Butyrates; D008358:Mannose; D014993:Xylitol