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W J Stec

Publications and source records attributed to W J Stec.

79 records · Page 5Linked to original sources
PubMed1977

The metabolism and antitumour activity of the enantiomers of cis- and trans-4-methylcyclophosphamide.

4-Methylcyclophosphamide, an analogue of the antitumour agent cyclophosphamide, exists in cis and trans forms, each of which comprises a pair of optical isomers. The extents of metabolism by rat liver microsomes during 20 min were compared for the four steroisomers incubated separately, and for the racemic cis and trans-derivatives in admixture, using mass spectrometry and gas chromatography respectively. In comparative antitumour tests against the ADJ/PC6 plasma cell tumour in mice, the racemic cis and trans forms of 4- and 6-methylcyclophosphamide had similar therapeutic indices. The four stereoisomers of 4-methylcyclophosphamide exhibited an approx. two-fold range in therapeutic index so that there was no marked effect on either metabolism or antitumour activity occasioned by change of configuration either at C-4 or at phosphorus.

Animals↗
PubMedDate not supplied

Modulation of plasminogen activator inhibitor type-1 biosynthesis in vitro and in vivo with oligo(nucleoside phosphorothioate)s and related constructs.

Oligonucleotides with a nucleotide sequence complementary to various regions of human plasminogen activator inhibitor type-1 (PAI-1) mRNA have been studied as antisense inhibitors of expression of PAI-1 protein in cultured cells [human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells, human hybrid endothelial cells]. Hexadeca(deoxyribonucleoside phosphorothioate) 13 complementary to a fragment of a signal peptide PAI-1 mRNA was found to be most active, giving ca. 70% inhibition of PAI-1 release in a time- and dose-dependent way. The stereo-regular All-S(P) and All-R(P) diastereomers of 13 were studied and found to inhibit PAI-1 synthesis in HUVEC in a stereo-dependent manner, with the All-S(P) diastereomer considerably more active than the stereo-random construct and All-R(P) isomer. The observed stereo-dependent activity of oligonucleotide phosphorothioate constructs is presumably governed by their resistance to nucleases. The corresponding phosphodiester analogue of 13 was not active unless covalently bound at its 5'-end to a lipophilic alcohol residue (menthol, heptadecanol). The observed antisense activity of phosphodiester oligonucleotide bioconjugates in cultured human hybrid endothelial cells was paralleled by their increased stability in human plasma with respect to unconjugated oligonucleotide. The oligo(deoxyribonucleoside phosphorothioate) complementary to the same signal peptide region of rat PAI-1 mRNA was found to reduce the PAI-1 level in blood plasma of rats after intravenous administration into the tail vein. The effect was both time- and dose-dependent. The same oligonucleotide was found to protect against arterial thrombus formation in the rat (lower incidence of venous thrombosis, lower thrombus weight, and increased occlusion time in experimentally induced thrombosis). An anti-PAI-1 inhibitory activity has been independently reported for a 20-mer oligo(2'-O-methyl-ribonucleoside phosphorothioate) complementary to a 3'-untranslated region of human PAI-1 mRNA in cultured HUVEC and human aortic smooth muscle cells.

Animals↗
PubMedDate not supplied

The cytotoxicity of anti-PAI-1 oligonucleotides and their conjugates.

The cytotoxicity of anti-PAI-5 hexadecanucleotides (phosphodiesters and phosphorothioates) and their conjugates with lipophilic alcohols was tested in EA.hy 926 hybrid endothelial cells. Some cytotoxicity was found for cholesteryl and bornyl conjugates at concentrations higher than those used for antisense inhibition experiments.

Cell Line↗
PubMedDate not supplied

Nucleophilic N1-->N3 rearrangement of 5'-O-trityl-O2,3'-cycloanhydrothymidine.

5'-O-Trityl-O2,3'-cycloanhydrothymidine (1) heated at 150 degrees C in the presence of O,O-diethyl phosphate or O,O-diethyl phosphorothioate anions undergoes rearrangement into N3-isomer (2); its structure was established by both advanced NMR methods and X-ray crystallographic studies. The most probable mechanism of 1-->2 rearrangement relies upon reversibility of glycosidic bond cleavage process.

Crystallography, X-Ray↗
PubMedDate not supplied

The synthesis of dithymidine boranophosphate by the oxathiaphospholane approach.

The application of the oxathiaphospholane approach for the synthesis of dithymidine boranphospate was evaluated. It was shown, that although the nucleoside-3'-O-oxathiaphospholane-borane complexes 2 or 6 could not be chromatographically separated into diastereomerically pure species due to their apparent instability to moisture, they can be successfully applied to the non-stereocontrolled formation of internucleotide boranophosphate bond by reaction with 5'-OH-nucleoside in the presence of DBU. Attempts to apply the related dithiaphospholane approach for the preparation of dithymidine boranophosphorothioate were unsuccessful.

Boron Compounds↗
PubMedDate not supplied

X-ray-diffraction study and determination of absolute configuration of the anticancer drug S(--)cyclophosphamide (Endoxan, Cytoxan, NSC-26271).

(--)Cyclophosphamide(1) crystallized from tetrachloromethane in the triclinic space group P1 with cell dimensions a = 10.500 (4) A, b = 10.490 (4) A, c = 10.761 (4) A, alpha = 110.0 (2) degrees, beta = 110.0 (2) degrees, gamma = 108.9 (2) degrees. Three molecules are contained in the unit cell. The X-ray analysis was based on diffractometer measurement of 2635 independent reflections and the structure was solved by Patterson and direct methods. The final R and Rw factors after full-matrix least-squares refinement are 0.0717 and 0.0677, respectively. The absolute configuration is S based on Hamilton's R-factor ratio test. The oxazaphosphorinane ring exists in a chair form with the bis-beta chloroethyl-amino group in equatorial position and about perpendicular to and bisecting the O--P--N plane. The structure is similar to that found in racemic 1 except a different conformation about one ethyl-amino N--C bond.

Cyclophosphamide↗