Structures of Lactate Dehydrogenase A (LDHA) In Apo, Ternary an Inhibitor-Bound Forms

Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD + as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known inhibitors of the human muscle LDH isoform, LDHA, designated 1 and 2 , were selected, and their IC 50 values were determined to be 14.4 ± 3.77 and 2.20 ± 0.15 µ M , respectively. The X-ray crystal structures of LDHA in complex with each inhibitor were determined; both inhibitors bind to a site overlapping with the NADH-binding site. Further, an apo LDHA crystal structure solved in a new space group is reported, as well as a complex with both NADH and the substrate analogue oxalate bound in seven of the eight molecules and an oxalate only bound in the eighth molecule in the asymmetric unit. In this latter structure, a kanamycin molecule is located in the inhibitor-binding site, thereby blocking NADH binding. These structures provide insights into LDHA enzyme mechanism and inhibition and a framework for structure-assisted drug design that may contribute to new cancer therapie

Copper(I) chloride and copper(I) cyanide-mediated transformations of alkenlytrialkylstannanes

A new synthetic method, involving the copper(I) mediated intramolecular conjugate addition of alkenyltrimethylstannanes to α,(β-unsaturated ketones, has been developed. Alkylated vinylogous esters of general structure 338 were prepared from vinylogous ester 120 and allylic bromide 128; these compounds were readily transformed via either reduction or Grignard addition, followed by hydrolysis and dehydration, into enones of general structure 150. Upon treatment with 2.5 equiv of CuCl in DMF, these enones afforded the functionalized bicyclo[4.3.0]non-8-en-3-ones having general structure 151. Enones 150 possessing sterically bulky R² groups gave poor yields when cyclized with CuCl; however, the use of CuCN in DMSO ameliorated this problem and produced superior results. Using a similar procedure, enones of general structure 46 were prepared from 189 (R³ = H or Me) and Afunctional reagents of general structure 190. Upon treatment with 2.5 equiv of CuCN in DMSO, enones 46 were converted into the corresponding bicyclic compounds 47. Subsequent intramolecular alkylation with potassium tert-butoxide in DMSO afforded the tricyclic ketones having general structure 48. Particularly noteworthy was the synthesis by this method of ketone 244, which possesses three contiguous quaternary centres. Using analogous procedures, dienones 251 and 51 were prepared from 120 and alkylating agents 128 and 190 via sequential bis-alkylation, reduction, hydrolysis/dehydration and dehydrogenation. Under the same conditions as described above (CuCN, DMSO), these substrates underwent one-pot tandem conjugate addition reactions to give tricyclic compounds 269 and 52, respectively. Interestingly, when cyclization of 251 was conducted in a sealed tube, the bridged structure 288 was formed as the major product. Treatment of chloro ketones 52 (n = 1, 2) with t-BuOK in DMSO resulted in tandem intramolecular alkylations to provide the pentacyclic compounds of general structure 53; similar attempts to cyclize 52 (n = 3) gave complex mixtures. A new, stereospecific CuCl-mediated intermolecular oxidative coupling reaction of alkenyltrialkylstannanes was also discovered, whereby (E)- and (Z)-3-trimethylstannylalk-2- enoates (90 and 92) as well as alkenylstannanes 365 were converted into conjugated dienes of general structure 91, 93, and 366, respectively, by treatment with 2.5 equiv of CuCl in DMF. New methods were also developed for the conversion of alkyl (Z)- and (E)-2,3- bis(trimethylstannyl)alk-2-enoates (102 and 103, respectively) into the E and Z isomers of the corresponding alkyl 3-trimethylstannylalk-2-enoates (90 and 92, respectively). Treatment of 102 with a catalytic amount of CuCl in DMF/H₂O afforded stereoselectively the E alkenoates 90, whereas treating either 102 or 103 with 1.2 equiv of IN aqueous HC1 in DMF afforded primarily the Z isomers 92. [chemical compound diagrams]Science, Faculty ofChemistry, Department ofGraduat

Magnetization and spin gap in two-dimensional organic ferrimagnet BIPNNBNO

A magnetization process in the two-dimensional ferrimagnet BIPNNBNO is analyzed. The compound consists of ferrimagnetic (1,1/2) chains coupled by two sorts of antiferromagnetic interaction. Whereas the behavior of the magnetization curve in higher magnetic fields can be understood within a process for the separate ferrimagnetic chain, the appearance of the singlet plateau at lower fields is an example of non-Lieb-Mattis type ferrimagnetism. By using the exact diagonalization technique for finite clusters of size 4×6, 4×8 and 4×10 we show that the interchain frustration coupling plays an essential role in stabilization of the singlet phase. These results are complemented by an analysis of four cylindrically coupled ferrimagnetic (1,1/2) chains via an Abelian bosonization technique and an effective theory based on the XXZ spin-1/2 Heisenberg model when the interchain interactions are sufficiently weak/strong, respectively. © 2012 IOP Publishing Ltd