2 research outputs found
On multiplicative structure in Quasi-Newton methods for nonlinear equations
We address the problem how additive and multiplicative structure in the derivatives can be exploited for the construction of Quasi-Newton approximations in smooth nonlinear equations. We derive a model algorithm and show its convergence properties based on a Broyden-like update rule. As a consequence of the use of exact multiplicative parts the convergence factor of the q-linear convergence rate is monotonically decreasing with the norm of the multiplicative part at the solution. Moreover, q-superlinear convergence can be shown, if certain compactness properties are valid, and q-quadratic convergence is obtained, if the multiplicative part vanishes at the solutionAvailable from TIB Hannover: RR 1843(92-22) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman
Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets
Psammaplin A (<b>11c</b>) is a marine metabolite
previously
reported to be a potent inhibitor of two classes of epigenetic enzymes:
histone deacetylases and DNA methyltransferases. The design and synthesis
of a focused library based on the psammaplin A core has been carried
out to probe the molecular features of this molecule responsible for
its activity. By direct in vitro assay of the free thiol generated
upon reduction of the dimeric psammaplin scaffold, we have unambiguously
demonstrated that <b>11c</b> functions as a natural prodrug,
with the reduced form being highly potent against HDAC1 in vitro (IC<sub>50</sub> 0.9 nM). Furthermore, we have shown it to have high isoform
selectivity, being 360-fold selective for HDAC1 over HDAC6 and more
than 1000-fold less potent against HDAC7 and HDAC8. SAR around our
focused library revealed a number of features, most notably the oxime
functionality to be important to this selectivity. Many of the compounds
show significant cytotoxicity in A549, MCF7, and W138 cells, with
the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore,
compound treatment causes upregulation of histone acetylation but
little effect on tubulin acetylation. Finally, we have found no evidence
for <b>11c</b> functioning as a DNMT inhibitor