Division of Medicinal Chemistry Abstracts-235th ACS National ...

MEDI 90
3-D-QSAR studies on benzothiadizapine hydroxamates as tumor necrosis factor-alpha
converting enzyme inhibitors
Prashant R. Murumkar, Pharmacy Department, The M. S. University of Baroda, Faculty of
Technology & Engineering, The M. S. University of Baroda, Kalabhavan, Vadodara, Gujarat
390001, India, Fax: +91-265-2018927, prashant_murumkar@yahoo.com, Rajani Giridhar,
Pharmacy Department, The M.S University of Baroda, vadodara 390002, India, and Mange
Ram Yadav, Department of pharmacy, The M.S University of Baroda, Baroda 390001, India
A set of twenty nine Benzothiadizepine hydroxamates having selective Tumor Necrosis factoralpha
converting enzyme inhibition activity were used to compare the quality and predictive
power of 3D-QSAR, CoMFA and CoMSIA models for the atom based , centroid–atom based,
data based and docked conformer based alignment. Removal of two outliers from the initial
training set of 29 molecules improved the predictivity of the models. Among the 3D-QSAR
models developed using the above four alignments, the database alignment provided the
optimal predictive CoMFA model for the training set with cross-validated r2 = 0.510, non-cross
validated r2 = 0.972, standard error of estimates (s) = 0.098 and F = 215.44 and the optimal
CoMSIA model with cross-validated r2 = 0.556, non-cross validated r2 = 0.946, standard error
of estimates (s) = 0.163 and F = 99.785. These models also showed the best test set prediction
for the 6 compounds with predictive r2 values of 0.460 and 0.535, respectively. The contour
maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules
analyzed. The CoMSIA models exhibited good external predictivity as compared to that of
CoMFA models. The data generated from the present study helped us to further design and
report some novel and potent TACE inhibitors.
MEDI 91
A nonclassical NF- κB pathway in HUVEC cells revealed by small molecule probes
Yidong Liu 1 , Gangli Gong 1 , Yuli Xie 1 , Alison Rinderspacher 1 , Shi-Xian Deng 1 , Donald W.
Landry 1 , Michael Wyler 2 , Nathalie Aulner 2 , Udo Toebben 2 , Deborah H. Smith 2 , Lars Branden 2 ,
Caty Chung 3 , Stephan Schürer 3 , and Dušica Vidović 3 . (1) Department of Medicine, Columbia
University, 650 W 168th St, BB 1029, New York, NY 10032, (2) Department of Physiology and
Cellular Biophysics, Columbia University, New York, NY 10032, (3) Scientific Computing, The
Scripps Research Institute, Jupiter, FL 33458
The nuclear translocation of NF-κB is an early event in the NF-κB pathway. Using small
molecule probes, we studied the translocation of P65 in human umbilical vein endothelial cells
(HUVEC). The results showed that the translocation was inhibited by known NF-κB pathway
inhibitors such as the proteasome inhibitor MG-132, the E3 ligase inhibitor Ro106-9920, nonspecific
IKK inhibitor Bay-11708. Intriguingly, the translocation was insensitive to a potent IKK2
inhibitor, suggesting that the classical IκB kinase type 2 is not involved in the pathway. To rule
out the cell permeability played a role, a series of analogs with hydrophobic side chains were
synthesized and all of them failed to inhibit the translocation. Another reported cell-permeable
IKK inhibitor was also tested and unexpectedly showed activation effect, possibly due to its nonspecific
activities. In summary, our results indicated that a non-classical NF-κB pathway might
involve in endothelial cells stimulation.