Synthesis of novel platinum oxadiazoline complexes with potential anti-tumour activity.

In the framework of this project, a series of platinum 4-1,2,4-oxadiazoline complexes was produced. These complexes were tested in vitro for anti-tumour effect and have been found to exhibit anti-tumour activity in ovarian, testicular-and colon cell cultures. One complex, JS5, trans-dichlorobis{2-methyl-3- phenyl-5-(4-hydroxyphenyl)-4-1,2,4-oxadiazoline}platinum(II), trans-[PtCl2{N=C(p-HO-C6H4)-0-N(Me)-CH(Ph)}2] (product 45), proved to be twice as effective as carboplatin and also showed good activity in carboplatin resistant cell lines. Another complex JS6, trans-dichloro(4-(2-methoxyethoxy)benzonitrile){2- methyl-3-phenyl-5-(4-(2-methoxyethoxy)phenyl)-4-1,2,4-oxadiazoline}platinum(II), trans-[PtCl2(p-Me0C2H40-C6H4CN){N=C(p-Me0C2H40-C6H4)-0-N(Me)-CH(Ph)}] (product 41), proved to be more effective in carboplatin resistant cell lines than platinum sensitive ones. This suggests a binding mode different to the accepted one exhibited by cisplatin, which is to the N7 nitrogen of guanine. The synthetic strategy employed was the [2+3] cycloaddition of platinum nitrile complexes to nitrones. This method was chosen as it is a straight forward route to the platinum heterocycles, using relatively mild conditions. Also, properties such as solubility of the platinum oxadiazoline in polar solvents can easily be modified by using starting nitrones and platinum nitriles that contain polar substituents. The stalling reagents for these compounds are commercially available, simplifying the overall synthesis. In this way the ligand is constructed in the coordination sphere and subtle changes are effected without altering the basic skeleton of the complex. Nitrones of the type RC6H4CH=NOCH3 (R= OH, CO2H, 2-CH3OC2H4O, N(Me)2, N+(Me)3, and sodium sulphonate salt), were prepared from the corresponding aldehydes via the condensation of an aldehyde with N-methyl-hydroxylamine method. Novel platinum complexes of the type PtX2(RC6H4CN)2, (X= halogen, R = OH, 2- CH3OC2H4O, were also prepared by a modification of the Kharasch route. Both mono and bis 4-1,2,4-oxadiazolme platinum complexes were produced that were more soluble in polar solvents than previously known similar complexes. Substitution and oxidative addition reactions of the said oxadiazoline platinum complexes were also studied and are discussed. The synthesis of analogous ruthenium complexes was attempted, but ruthenium did not behave in the same way as platinum

Synthesis of novel platinum oxadiazoline complexes with potential anti-tumour activity.

In the framework of this project, a series of platinum 4-1,2,4-oxadiazoline complexes was produced. These complexes were tested in vitro for anti-tumour effect and have been found to exhibit anti-tumour activity in ovarian, testicular-and colon cell cultures. One complex, JS5, trans-dichlorobis{2-methyl-3- phenyl-5-(4-hydroxyphenyl)-4-1,2,4-oxadiazoline}platinum(II), trans-[PtCl2{N=C(p-HO-C6H4)-0-N(Me)-CH(Ph)}2] (product 45), proved to be twice as effective as carboplatin and also showed good activity in carboplatin resistant cell lines. Another complex JS6, trans-dichloro(4-(2-methoxyethoxy)benzonitrile){2- methyl-3-phenyl-5-(4-(2-methoxyethoxy)phenyl)-4-1,2,4-oxadiazoline}platinum(II), trans-[PtCl2(p-Me0C2H40-C6H4CN){N=C(p-Me0C2H40-C6H4)-0-N(Me)-CH(Ph)}] (product 41), proved to be more effective in carboplatin resistant cell lines than platinum sensitive ones. This suggests a binding mode different to the accepted one exhibited by cisplatin, which is to the N7 nitrogen of guanine. The synthetic strategy employed was the [2+3] cycloaddition of platinum nitrile complexes to nitrones. This method was chosen as it is a straight forward route to the platinum heterocycles, using relatively mild conditions. Also, properties such as solubility of the platinum oxadiazoline in polar solvents can easily be modified by using starting nitrones and platinum nitriles that contain polar substituents. The stalling reagents for these compounds are commercially available, simplifying the overall synthesis. In this way the ligand is constructed in the coordination sphere and subtle changes are effected without altering the basic skeleton of the complex. Nitrones of the type RC6H4CH=NOCH3 (R= OH, CO2H, 2-CH3OC2H4O, N(Me)2, N+(Me)3, and sodium sulphonate salt), were prepared from the corresponding aldehydes via the condensation of an aldehyde with N-methyl-hydroxylamine method. Novel platinum complexes of the type PtX2(RC6H4CN)2, (X= halogen, R = OH, 2- CH3OC2H4O, were also prepared by a modification of the Kharasch route. Both mono and bis 4-1,2,4-oxadiazolme platinum complexes were produced that were more soluble in polar solvents than previously known similar complexes. Substitution and oxidative addition reactions of the said oxadiazoline platinum complexes were also studied and are discussed. The synthesis of analogous ruthenium complexes was attempted, but ruthenium did not behave in the same way as platinum

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article