Virtual and experimental high-throughput screening (HTS) in search of novel inosine 5′-monophosphate dehydrogenase II (IMPDH II) inhibitors

IMPDH (Inosine 5??-monophosphate dehydrogenase) catalyzes a rate-limiting step in the de novo biosynthesis of guanine nucleotides. IMPDH inhibition in sensitive cell types (e.g., lymphocytes) blocks proliferation (by blocking RNA and DNA synthesis as a result of decreased cellular levels of guanine nucleotides). This makes it an interesting target for cancer and autoimmune disorders. Currently available IMPDH inhibitors such as mycophenolic acid (MPA, uncompetitive inhibitor) and nucleoside analogs (e.g., ribavirin, competitive inhibitor after intracellular activation by phosphorylation) have unfavorable tolerability profiles which limit their use. Hence, the quest for novel IMPDH inhibitors continues. In the present study, a ligand-based virtual screening using IMPDH inhibitor pharmacophore models was performed on in-house compound collection. A total of 50,000 virtual hits were selected for primary screen using in vitro IMPDH II inhibition up to 10???M. The list of 2,500 hits (with >70?% inhibition) was further subjected to hit confirmation for the determination of IC₅₀ values. The hits obtained were further clustered using maximum common substructure based formalism resulting in 90 classes and 7 singletons. A thorough inspection of these yielded 7 interesting classes in terms of mini-SAR with IC₅₀ values ranging from 0.163???M to little over 25???M. The average ligand efficiency was found to be 0.3 for the best class. The classes thus discovered represent structurally novel chemotypes which can be taken up for further development.     

List Homomorphisms and Circular Arc Graphs

G , H, and lists , a list homomorphism of G to H with respect to the lists L is a mapping , such that for all , and for all . The list homomorphism problem for a fixed graph H asks whether or not an input graph G together with lists , , admits a list homomorphism with respect to L. We have introduced the list homomorphism problem in an earlier paper, and proved there that for reflexive graphs H (that is, for graphs H in which every vertex has a loop), the problem is polynomial time solvable if H is an interval graph, and is NP-complete otherwise. Here we consider graphs H without loops, and find that the problem is closely related to circular arc graphs. We show that the list homomorphism problem is polynomial time solvable if the complement of H is a circular arc graph of clique covering number two, and is NP-complete otherwise. For the purposes of the proof we give a new characterization of circular arc graphs of clique covering number two, by the absence of a structure analogous to Gallai's asteroids. Both results point to a surprising similarity between interval graphs and the complements of circular arc graphs of clique covering number two. Received: July 22, 1996/Revised: Revised June 10, 1998     

Heterogeneous catalytic 1,4-addition of arylmagnesium compounds to chalcones

Copper(II) on a 4?Å molecular sieve support catalyses the chemoselective addition of alkyl- and arylmagnesium halides to chalcones. Only the 1,4-addition products were obtained in high yields.     

“Reduced” Coumarin Dyes with an O‐Phosphorylated 2,2‐Dimethyl‐4‐(hydroxymethyl)‐1,2,3,4‐tetrahydroquinoline Fragment: Synthesis,Spectra, and STED Microscopy

Large Stokes‐shift coumarin dyes with an O‐phosphorylated 4‐(hydroxymethyl)‐2,2‐dimethyl‐1,2,3,4‐tetrahydroquinoline fragment emitting in the blue, green, and red regions of the visible spectrum were synthesized. For this purpose, N‐substituted and O‐protected 1,2‐dihydro‐7‐hydroxy‐2,2,4‐trimethylquinoline was oxidized with SeO₂ to the corresponding α,β‐unsaturated aldehyde and then reduced with NaBH₄ in a “one‐pot” fashion to yield N‐substituted and 7‐O‐protected 4‐(hydroxymethyl)‐7‐hydroxy‐2,2‐dimethyl‐1,2,3,4‐tetrahydroquinoline as a common precursor to all the coumarin dyes reported here. The photophysical properties of the new dyes (“reduced coumarins”) and 1,2‐dihydroquinoline analogues (formal precursors) with a trisubstituted C=C bond were compared. The “reduced coumarins” were found to be more photoresistant and brighter than their 1,2‐dihydroquinoline counterparts. Free carboxylate analogues, as well as their antibody conjugates (obtained from N‐hydroxysuccinimidyl esters) were also prepared. All studied conjugates with secondary antibodies afforded high specificity and were suitable for fluorescence microscopy. The red‐emitting coumarin dye bearing a betaine fragment at the C‐3‐position showed excellent performance in stimulation emission depletion (STED) microscopy.     

On multiplicative graphs and the product conjecture

We study the following problem: which graphsG have the property that the class of all graphs not admitting a homomorphism intoG is closed under taking the product (conjunction)? Whether all undirected complete graphs have the property is a longstanding open problem due to S. Hedetniemi. We prove that all odd undirected cycles and all prime-power directed cycles have the property. The former result provides the first non-trivial infinite family of undirected graphs known to have the property, and the latter result verifies a conjecture of Ne?et?il and Pultr These results allow us (in conjunction with earlier results of Ne?et?il and Pultr [17], cf also [7]) to completely characterize all (finite and infinite, directed and undirected) paths and cycles having the property. We also derive the property for a wide class of 3-chromatic graphs studied by Gerards, [5].     

Stereoselective trans-reduktion tert. Propargylamine mit DIBAH zu (E)-Allylaminen

The reduction of tertiary propargylamines with DIBAH in toluene affords high yields of allylamines with trans-configuration exclusively.     

Menthatrienes and the Oxidation of Limonene

The oxidation of limonene with mercuric acetate gives a mixture containing mentha-1. 3. 8-triene, the hydrocarbon of parsley, and its isomer, mentha-1. 4. 8-triene. Selenium dioxide oxidation of limonene in alcohol gives as the main product mentha-1. 8-dien-4-ol, and pyrolysis of the acetate of the latter, or of mentha-1. 8-dien-10-yl acetate (the main product of the oxidation of limonene with selenium dioxide in acetic anhydride), also gives a mixture of menthatrienes. A discussion of the selenium dioxide oxidation of limonene is presented.