Two Novel Mouse Models of Duchenne Muscular Dystrophy with Similar Dmd Exon 51 Frameshift Mutations and Varied Phenotype Severity.

Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by an array of mutations in the dystrophin gene, with the most commonly mutated regions being exons 48-55. One of the several existing approaches to treat DMD is gene therapy, based on alternative splicing and mutant exon skipping. Testing of such therapy requires animal models that carry mutations homologous to those found in human patients.

Ursolic acid-based 24-nor- and A--24-oxy-triterpenoids.

Using methyl 2-cyano-3,4--12(13),4(23)-diene-ursolate as a starting scaffold a series of 3-oxo-24-nor-ursolate and A--ursanes holding hydroxy-, furoyloxy-, -tosyloxy- as well as aldehyde fragments at C24 that possess cytotoxic activity has been synthesised. The structures of the new ursanes were confirmed by detailed spectral data analysis. The chemoselectivity of methyl 2-cyano-3,4--12(13),4(23)-diene-ursolate oxidation involving the double bond in the A cycle was observed.

An unexpected conversion of 2E-furfurylidene-3-oxo-24-nor-allobetulin to 23-nor-allobetulins.

A series of 2E-furfurylidene-23-nor- and 24-nor-allobetulins has been synthesized by the Claisen-Schmidt condensation and conditions of their formation were studied in detail. It was found that among an expected 2E-furfurylidene-3-oxo-24-nor-allobetulin 4 two byproducts holding 3-oxo-4α-hydroxy- 5 and 3β,4α-dihydroxy- 6 substituents were formed, which could become the main products under the change of reaction time and amount of the base solution. Moreover, a conversion of individual 2E-furfurylidene-23-nor-3-oxo-4α-hydroxy- 5 into 2E-furfurylidene-23-nor-3β,4α-dihydroxy-derivative 6 under the treatment with the base solution was observed.

24-Nor-allobetulins possess strong α-glucosidase inhibitory activity.

A series of 24-nor-allobetulin derivatives holding 3β-hydroxy-, oxime, methoxyoxime, lactame and 4-bromobenzylidene substituents have been synthesized and their differences in the NMR spectra were studied in detail. It was revealed that 3-oxo-24-nor-allobetulin loses selectivity in the reaction of oximation and forms a mixture of oximes (and methoxyoximes) in contract to the related derivatives of native scaffold (that forms only -isomers). The screening of α-glucosidase inhibitory activity revealed that 24-nor-allobetulins are more active than allobetulins.

Novel Synthesized -Ethyl-Piperazinyl-Amides of C2-Substituted Oleanonic and Ursonic Acids Exhibit Cytotoxic Effects through Apoptotic Cell Death Regulation.

A series of novel hybrid chalcone N-ethyl-piperazinyl amide derivatives of oleanonic and ursonic acids were synthesized, and their cytotoxic potential was evaluated in vitro against the NCI-60 cancer cell line panel. Compounds and exhibited the highest overall anticancer activity, with GI values in some cases reaching nanomolar values. Thus, the two compounds were further assessed in detail in order to identify a possible apoptosis- and antiangiogenic-based mechanism of action induced by the assessed compounds.