Stefan Kwiatkowski
University of Kentucky
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Featured researches published by Stefan Kwiatkowski.
Tetrahedron Letters | 1990
Stefan Kwiatkowski; Peter J. Crocker; Ashok J. Chavan; Imai Nobuyuki; Boyd E. Haley; David S. Watt
Abstract The condensation of cysteine with 3-(4-formylphenyl) or 3-(4-cyanophenyl)-3-trifluoromethyldiazirine furnished thiazolidine and thiazoline derivatives in good yield. These heterocycles provide convenient access to photoaffinity probes an 35 S radiolabel or a fluorescent dansyl group.
Journal of Chemical Information and Modeling | 2014
Adel Hamza; Jonathan M. Wagner; Ning-Ning Wei; Stefan Kwiatkowski; Chang-Guo Zhan; David S. Watt; Konstantin V. Korotkov
Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza–Wei–Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 μM against MycP1 and possessed high structural diversity, which provides departure points for further structure–activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy.
Bioorganic & Medicinal Chemistry Letters | 2014
Mykhaylo S. Frasinyuk; Stefan Kwiatkowski; Jonathan M. Wagner; Timothy J. Evans; Robert W. Reed; Konstantin V. Korotkov; David S. Watt
Mycosin protease-1 (MycP1) cleaves ESX secretion-associated protein B (EspB) that is a virulence factor of Mycobacterium tuberculosis, and accommodates an octapeptide, AVKAASLG, as a short peptide substrate. Because peptidoboronic acids are known inhibitors of serine proteases, the synthesis and binding of a boronic acid analog of the pentapeptide cleavage product, AVKAA, was studied using MycP1 variants from Mycobacterium thermoresistible (MycP1mth), Mycobacterium smegmatis (MycP1msm) and M. tuberculosis (MycP1mtu). We synthesized the boropentapeptide, HAlaValLysAlaAlaB(OH)2 (1) and the analogous pinanediol PD-protected HAlaValLysAlaAlaBO2(PD) (2) using an Fmoc/Boc peptide strategy. The pinanediol boropentapeptide 2 displayed IC50 values 121.6±25.3 μM for MycP1mth, 93.2±37.3 μM for MycP1msm and 37.9±5.2 μM for MycP1mtu. Such relatively strong binding creates a chance for crystalizing the complex with 2 and finding the structure of the unknown MycP1 catalytic site that would potentially facilitate the development of new anti-tuberculosis drugs.
Inhalation Toxicology | 1993
S. Stanley; C. G. Gairola; J. Diana; M. Huffman; R. Sadove; W. E. Woods; Stefan Kwiatkowski; Tai Hh; Thomas Tobin
AbstractCotinine is a major metabolite of nicotine and serves as an important biomarker of tobacco smoke exposure. To monitor exposure to tobacco smoke or nicotine, a sensitive enzyme-linked immunosorbent assay (ELISA) for cotinine was developed. The test had an 1–50 of between 0.5 and 1.0 ng/ml for cotinine and about 500-fold less affinity for nicotine. Few matrix effects were not detectable in human saliva, although relatively small matrix effects (1–50 for cotinine, 2.8 ng/ml) were observed in human serum and urine. The test accurately measured the levels of cotinine in NI5T standards in freeze-dried human urine derivative material (r = .9999) indicating its reliability for measurement of cotinine. The test readily detected low levels (5–500 nglml) of cotinine in human saliva and serum samples. Also, the levels of cotinine in plasma and urine samples from smoke-exposed mice and rats could be rapidly analyzed for cotinine. This ELISA is therefore a sensitive and accurate test for the determination of co...
Bioorganic & Medicinal Chemistry Letters | 2016
Stefan Kwiatkowski; Vitaliy M. Sviripa; Zhaiyi Zhang; Alison E. Wendlandt; Claudia Höbartner; David S. Watt; Stefan Stamm
Phosphorylation and dephosphorylation of splicing factors play a key role in pre-mRNA splicing events, and cantharidin and norcantharidin analogs inhibit protein phosphatase-1 (PP1) and change alternative pre-mRNA splicing. Targeted inhibitors capable of selectively inhibiting PP-1 could promote exon 7 inclusion in the survival-of-motorneuron-2 gene (SMN2) and shift the proportion of SMN2 protein from a dysfunctional to a functional form. As a prelude to the development of norcantharidin-tethered oligonucleotide inhibitors, the synthesis a norcantharidin-tethered guanosine was developed in which a suitable tether prevented the undesired cyclization of norcantharidin monoamides to imides and possessed a secondary amine terminus suited to the synthesis of oligonucleotides analogs. Application of this methodology led to the synthesis of a diastereomeric mixture of norcantharidin-tethered guanosines, namely bisammonium (1R,2S,3R,4S)- and (1S,2R,3S,4R)-3-((4-(2-(((((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-yl)oxy)oxidophosphoryl)oxy)ethyl)-phenethyl)(methyl)carbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylate, which showed activity in an assay for SMN2 pre-mRNA splicing.
Bioconjugate Chemistry | 1991
Matthew S. Platz; Stefan Kwiatkowski; Peter J. Crocker; Nobuyuki Imai; David S. Watt
Bioconjugate Chemistry | 1990
Peter J. Crocker; Nobuyuki Imai; Krishnan Rajagopalan; Michael A. Boggess; Stefan Kwiatkowski; Lori D. Dwyer; Thomas C. Vanaman; David S. Watt
Synthesis | 1989
Stefan Kwiatkowski; Ashfaq Syed; Carolyn Pratt Brock; David S. Watt
Research communications in chemical pathology and pharmacology | 1988
Thomas Tobin; David S. Watt; Stefan Kwiatkowski; Tai Hh; Blake Jw; J. Mcdonald; Prange Ca; S. Wie
Synthesis | 1989
Stefan Kwiatkowski; Azhwarsamy Jeganathan; Thomas Tobin; David S. Watt