Barry Goz

Boronic Acid Derivatives Targeting HIV-1

A series of novel boronic acid derivatives containing either a pyrimidine or purine base was synthesized. The preparation involved the condensation of 4-bromobutyl boronic acid with the appropriate base. These acyclic nucleosides were designed as potential antiviral agents especially targeting the human immunodeficiency virus. Two analogues, 6-chloro-9-(4-dihydroxyborylbutyl)purine and 2,6-dichloro-9-(4-dihydroxyborylbutyl)purine, exhibited EC50 values of 7.7 μM and 0.99 μM, respectively, in an HIV-1 syncytial plaque reduction assay.

Induction of reversible protein-linked DNA breaks in human osteogenic sarcoma cells by novel cytocidal colchicine derivatives which inhibit DNA topoisomerase II in vitro: Absence of cross-resistance in a colchicine-resistant sub-clone

Abstract Two colchicine derivatives gave dose-dependent cytocidal effects in human osteogenic sarcoma cells. Unlike colchicine, the analogues stimulated formation of intacellular protein-linked DNA breaks, they inhibited DNA topoisomerase II in vitro, and their cytotoxic action was not modulated by the P-glycoprotein drug-efflux pump.

Compounds that inhibit chymotrypsin and cell replication

Several compounds have been tested for their ability to inhibit bovine pancreatic alpha-chymotrypsin (Ki) and their ability to inhibit cell replication (IC50). There is good agreement over three orders of magnitude between the Ki and the IC50 values of these compounds. The data support the hypothesis that a cellular, chymotrypsin-like activity is necessary for cell replication.

Induction of alkaline phosphatase activity in hela cells: Inhibition by xanthine derivatives and thermostability studies

Abstract The induction of alkaline phosphate activity in HeLa cells by 5-iodo-2′-deoxyuridine (IUdR) or hydrocortisone was inhibited in a dose-dependent manner by the addition of the xanthine derivatives caffeine, theophylline or 3-isobutyl-1-methylxanthine to the culture medium during the 72 hr of the induction. Pretreatment with theophylline from −24 to 0 hr or treatment from 0 to 24 hr with any of the xanthine derivatives was ineffective in inhibiting alkaline phosphatase induction produced by treatment with IUdR from 0 to 72 hr. The induction of alkaline phosphatase activity produced by treatment with hydrocortisone from 0 to 72 hr was inhibited by pretreatment with theophylline from −24 to 0 hr, although this inhibition was only about 60 per cent as great as that seen with treatment from 0 to 72 hr. As judged by heat inactivation studies, IUdR predominantly increased the heat-labile form of alkaline phosphatase activity, while hydrocortisone predominantly increased the heat-stable form. Regardless of the inducer used, the xanthine derivatives mainly decreased the heat-stable form of alkaline phosphatase activity. Treatment with imidazole over a 72-hr period produced over a 2-fold induction of alkaline phosphatase activity, which could be inhibited completely by concurrent treatment with theophylline.

Antiviral Activity of Iodinated Pyrimidine Deoxyribonucleosides

The nucleoside analogs AIdUrd, IdUrd and IdCyd exert their antiviral effects after phosphorylation and subsequent incorporation into viral DNA. AldUrd and IdCyd require the herpesvirus pyrimidine deoxyriboside kinase for the initial phosphorylation, but IdUrd is substrate for both the viral and cellular thymidine kinase. The incorporation into the viral DNA is a critical event in the antiviral action of these analogs. Their incorporation results in altered expression of viral specific RNA and proteins and the production of an abnormal population of virions with lowered specific infectivity and the ability to interfere with the replication of standard herpesvirus.

Induction of alkaline phosphatase activity in HeLa cells by sodium butyrate.

SummaryThe induction of HeLa cell alkaline phosphatase activity by sodium butyrate could be inhibited by the coadministration of caffeine or theophylline. The inhibitions were dose dependent, and at any given concentration the potency was theophylline > caffeine. Although the induction by sodium butyrate was more sensitive to the inhibition by the xanthines than was that produced by 5-iodo-2′-deoxyuridine, the magnitudes of the increases in cyclic AMP concentrations after treatment with the xanthines were similar in the inhibition of both types of induction. The induction of alkaline phosphatase activity by sodium butyrate also produced a shift in the thermostability pattern of the enzyme, with a proportionately greater increase in the heat-labile, rather than heat-stable, from of the activity.

Parathyroid hormone inhibition of induction of alkaline phosphatase activity by hydrocortisone and 5-iodo-2'-deoxyuridine in HeLa cells.

Abstract Parathyroid hormone blocked the induction by hydrocortisone or IUdR of alkaline phosphatase activity in HeLa S3 cells. Alkaline phosphatase activity was not affected by parathyroid hormone treatment alone. Parathyroid hormone added to cells preinduced with hydrocortisone prevented further induction of alkaline phosphatase activity and caused an eventual return of activity to the non-induced level.

Parathyroid hormone inhibition of induction of alkaline phosphatase activity in HeLa cells by 5-iodo-2′-deoxyuridine without increased adenylate cyclase activity or cellular cAMP concentration

Abstract Parathyroid extract (PTE) as well as purified parathyroid hormone (PTH) activators of adenylate cyclase in bone and kidney, produced dose-dependent decreases in the induction of alkaline phosphatase activity by 5-iodo-2′-deoxyuridine in HeLa cells. However, the combination of PTE and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor which also inhibits the induction of alkaline phosphatase activity, in most cases produced less than additive inhibition of enzyme induction. PTE or PTH in concentrations of up to 10 times greater than that necessary to have maximal effects on the induction of alkaline phosphatase activity produced no increase in adenylate cyclase activity, nor did they increase intracellular cAMP concentrations. In addition, PTE did not potentiate the increase in cAMP concentration produced by IBMX. It thus appears that the inhibition of alkaline phosphatase activity by PTH is not mediated by cAMP.

5-Iodo-2′-deoxyuridine inhibition of Dictyostelium discoideum differentiation and cyclic AMP phosphodiesterase activity

Abstract 5-Iodo-2′-deoxyuridine (IdUrd), at a concentration of 0.25 mM, had little or no effect on the growth of Dictyostelium discoideum for at least four doubling times. However, when these cells were allowed to differentiate, the number of fruiting bodies obtained was only about half of that obtained from cells grown in normal medium, and a great majority of them were about 1 4 to 1 8 the size of normal fruiting bodies. The inhibition of differentiation could be reversed if the cells were washed free of IdUrd and grown in normal medium for two generations before differentiation. If the IdUrd-grown cells were mixed with only 15 per cent as many normal cells just prior to differentiation, there was no inhibition of differentiation. Since it is known that, as a thymidine analogue, IdUrd can be incorporated into DNA, the induction patterns of several enzymes during growth and differentiation were compared in normal and IdUrd-treated cells. There was a continuous increase in the treated relative to untreated cells in the activities of the enzymes N-acetyl-glucosaminidase, α-mannosidase, β-glucosidase and acid and alkaline phosphatases during growth. There was also an increase in activity relative to control cells for all of these enzymes except alkaline phosphatase during the differentiation of cells previously grown in medium containing IdUrd. The reverse, however, was found for 3′,5′-cyclic adenosine monophosphate (cAMP) phosphodiesterase. There was a decrease caused by IdUrd in both the extracellular and cellular phosphodiesterase activity during development. In contrast, during growth, although IdUrd treatment also reduced the extracellular phosphodiesterase activity, the cellular phosphodiesterase activity remained unchanged from control.