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A Nechaev

Publications and source records attributed to A Nechaev.

10 recordsLinked to original sources
PubMed1990

Nucleoside conjugates. 11. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine and cytidine conjugates of thioether lipids.

Five 1-beta-D-arabinofuranosylcytosine conjugates and two cytidine conjugates of thioether lipids (1-S-alkylthioglycerols) linked by a pyrophosphate diester bond have been prepared and their antitumor activity against an ara-C2 sensitive (L1210/0) and two ara-C resistant L1210 lymphoid leukemia sublines in mice were evaluated. These prodrugs of ara-C include ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (8a), ara-CDP-rac-1-S-octadecyl-2-O-palmitoylthioglycerol (8b), and ara-CDP-rac-1-S-octadecyl-2-O-methyl(or -ethyl, -hexadecyl)thioglycerols (8c-e). The cytidine conjugates include CDP-rac-1-S-octadecyl-2-O-palmitoyl(or -methyl)- 1-thioglycerols (9a and 9b). Sonicated solutions of the conjugates existed in the form of micellar disks (size 0.01-0.04 microns). Single doses (200-400 mg/kg) of 8a and 8b produced significant increase in life span (257-371%) in mice bearing ip implanted L1210/0 leukemia. In contrast, conjugates 8c-e were less effective (ILS 19-75%) and cytidine conjugates (9a and 9b) were ineffective. Even though 8a and 8b were found to be curative in a high percentage of mice bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C(I)], they were completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C(II)]. However, the present results, together with the previous, demonstrate that 8a and 8b are promising new prodrugs of ara-C with improved efficacy.

Animals↗
PubMed1988

Nucleoside conjugates. 10. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitins.

Three 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitins from L-, D-, and DL-alpha-dipalmitoylphosphatidic acids have been synthesized and their antitumor activity against two ara-C2 resistant L1210 lymphoid leukemia sublines in mice were evaluated. These new prodrugs of ara-C include ara-CDP-L-dipalmitin, ara-CDP-D-dipalmitin, and ara-CDP-DL-dipalmitin. The L and DL isomers produced significant increase in life span (greater than 400%) and four to five long-term survivors (greater than 45 days) out of six animals bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C (I)], while the D isomer displayed a marginal activity (ILS 100-121%). In contrast, the L isomer was completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C (II)]. However, the results demonstrate that the L and DL isomers of ara-CDP-dipalmitin are promising new prodrugs of ara-C with improved efficacy.

Animals↗
PubMed1986

Nucleoside conjugates. 7. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of ether lipids.

Three new 1-beta-D-arabinofuranosylcytosine conjugates of ether lipids (alkyl glycerols) linked by a pyrophosphate diester bond have been prepared and evaluated against mouse leukemia L1210 and P388. These include ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (9a) (ara-CDP = 1-beta-D-arabinofuranosylcytosine 5'-diphosphate), ara-CDP-rac-1-O-octadecyl-2-O-palmitoylglycerol (9b), and ara-CDP-rac-1-O-octadecyl-2-O-methylglycerol (9c). Among them, conjugate 9a produced significant increase in life span (200-293%) in mice bearing ip and ic implanted L1210 lymphoic leukemia at a total dose of 400-500 mg (406-508 mumol/kg). Significant schedule dependence was not observed when the conjugate was given ip once daily on day 1, days 1, 5, and 9, and days 1-5. The new conjugates are water soluble by sonication.

Animals↗
PubMed1986

1-beta-D-arabinofuranosylcytosine conjugates of thioether phospholipids as a new class of potential antitumor drugs.

Three 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates of 1-S-alkyl-phospholipids (thioether phospholipids) were tested for their antitumor efficacies against L1210 and P388 leukemia in mice. These include 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-rac-1-S-hexadecyl-2-0-palmitoyl-1-thioglycerol (ara-CDP-beta-palmitoyl-DL-thiochimyl alcohol, I), ara-CDP-rac-1-S-octadecyl-2-0-palmitoyl-1-thioglycerol (ara-CDP-beta-palmitoyl-DL-thiobatyl alcohol, II), and ara-CDP-rac-1-S-octadecyl-2-0-hexadecyl-1-thioglycerol (ara-CDP-beta-cetyl-DL-thiobatyl alcohol, III). Conjugates I and II produced significant increase in life span (293-379%) and longterm survivors among mice bearing i.p. implanted L1210 lymphoid leukemia at a total dose of 400 mg (389-400 mumol)/kg. Conjugate II also displayed a strong antitumor activity against i.c. implanted L1210 leukemia in mice with an ILS range of 160-200% at a total dose of 300-450 mg (292-438 mumol/kg. Significant schedule dependency was not observed when the conjugates were administered i.p. once daily with following schedules: qd l; 1,5, 9; 1-5; and 1-9, but single doses typically produced the best effects. The i.p. administration of conjugate II gave the best results on survival of i.p. inoculated L1210 leukemic mice, then followed by the s.c. and i.m. treatments. The i.v. treatment produced a lower activity than the others. Conjugate II also exhibited a strong antitumor activity against i.p. implanted P388 leukemia in mice with ILS values of greater than 255-greater than 329% with 3-5 45-day survivors at a total dose of 300-500 mg (292-486 mumol)/kg (qd 1 or 1-5). The new conjugates I and II displayed a comparable or somewhat higher activity than the previous diacyl and 1-0-alkyl analogs.

Animals↗
PubMed1985

Nucleoside conjugates. 6. Synthesis and comparison of antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of corticosteroids and selected lipophilic alcohols.

Five new P1-(steroid-21-yl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyro phosphates (ara-CDP-steroids), five 1-beta-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyrophosphat e (ara-CDP-alkyl esters) have been prepared and evaluated against L1210 lymphoid leukemia in culture and in mice (C3D2F1/J). These include ara-CDP-11-deoxycorticosterone (6a), ara-CDP-cortisone (6c), ara-CDP-corticosterone (6d), ara-CDP-cortexolone (6e), and ara-CDP-prednisone (6g), ara-CMP hexadecyl ester (7a), ara-CMP 1-cyclohexylmethyl ester (7b), ara-CMP 1-adamantylmethyl ester (7c), ara-CMP 2-(1-adamanthyl)ethyl ester (7d), ara-CMP 2-chloroethyl ester (7e), ara-CDP hexadecyl ester (9a), and ara-CDP 1-cyclohexylmethyl ester (9b). The in vitro antitumor results indicated that ara-CDP-steroids were as active as the previously reported ara-CMP-steroids and that ara-CMP and ara-CDP-alkyl esters were less growth inhibiting than ara-CDP-steroids and ara-C. However, the in vivo antitumor results indicated that ara-CDP-steroids were generally less effective than the previous monophosphate derivatives. Among them ara-CDP-corticosterone (6d) and the known ara-CDP-cortisol (6b) showed greater efficacy than ara-C with ILS value of 152% and 209%, respectively, at the optimal dose of 40 and 80 (mg/kg)/day for 9 days, while that of ara-C was 138% at the optimum dose of 9.2 (mg/kg)/day. Generally, ara-CMP alkyl esters (7a-e), given ip to the L1210 leukemic mice, were found to be toxic and ineffective. However, ara-CDP hexadecyl ester (9a) showed marginal activity (ILS, 38%). These preliminary results support the thesis that the ara-C conjugates of this type may require a lipophilic and naturally occurring moiety for improved efficacy.

Adrenal Cortex Hormones↗
PubMed1979

Nucleoside conjugates as potential antitumor agents. 2. Synthesis and biological activity of 1-(beta-D-arabinofuranosyl)cytosine conjugates of prednisolone and prednisone.

Two of the new anticancer drugs recently synthesized in our laboratory from conjugation of ara-C2 and several corticosteroids linked through a phosphodiester bond include prednisolone- (I) and prednisone-p-ara-C (II). They were demonstrated to be enzymatically hydrolyzed to the corresponding steroid and ara-CMP and the latter was further shown to be hydrolyzed to ara-C by phosphodiesterase I, snake venom, 5'-nucleotidase, and acid phosphatase. However, the conjugates were shown to be resistant to hydrolysis by alkaline phosphatase. The activity of conjugates I and II against L1210 lymphoid leukemia in female mice (C3D2F1/J) was significantly greater than that of ara-C alone or in combination with the steroid. In fact, when the optimum dosage of 75 (mumol/kg)/day x 5 was used, the administration of ara-C alone was followed by an increased life span (ILS) of 45%. This result is similar to that previously reported. With the same equimolar doses of mixtures of ara-C and either prednisolone or prednisone, the ILS values were 40 and 44%, respectively. However, when the conjugates were used, the ILS values were 89 and 100% respectively. These findings seem promising and have provided the bases for continued study of these new compounds.

Animals↗
PubMed1977

Synergism between the antiproliferative activities of arabinosyladenine and N6-benzyladenosine.

N6-Benzyladenosine is a competitive inhibitor of adenosine deaminase from L-1210 cells in axenic culture as well as a potent antiproliferative agent in vitro and in vivo. Potentiation of the growth inhibitory activity of 9-beta-D-arabinosyladenine (ara-A) was observed in the L-1210 system with maximum synergism with a mixture of 16 micron ara-A and 10 micron benzyladenosine. Kinetic studies with L-1210 cell lysates showed values for Km of 0.25 mM ara-A and Ki of 0.23 mM benzyladenosine. It is suggested that ara-A and benzyladenosine in suitable combination may be expected to demonstrate enhanced clinical chemotherapeutic effectiveness.

Adenosine↗
PubMed1976

Cosolvent-buffer mixtures as models for the cytoplasmic mileu: the enzymology of adenosine aminohydrolase.

Adenosine aminohydrolase from calf intestinal mucosa is sensitive to changes in its environment produced by small mole fractions of dimethylsulfoxide (DMSO). At a mole fraction of 0.1 where the dielectric constant is lowered from that of 78 of neat water to about 76.5, Vmax was reduced by 65% and affinity for substrate (adenosine) and the two competitive inhibitors, insine and N6-benzyladenosine, was decreased markedly. However, this decreased affinity was such that Ki/Km remained virtually constant for both inhibitors. DMSO itself showed the kinetics of a mixed inhibitor with Ki decreasing with increasing mole fraction. This cosolvent also decreased the heat stability of the enzyme which suggests that enzyme conformation is altered by DMSO. Comparison of data in the presence of DMSO with previously obtained data with dioxane shows that heat stability as well as Vmax, at a given value of dielectric constant, is independent of the amount or nature of cosolvent used to achieve that dielectric constant. However, cosolvent induced changes in Ki indicate that colligative as well as dielectric constant effects contribute to the observed changes in kinetic behavior. These experiments may be considered as models for the behavior of enzymes in the medium of lowered dielectric constant expected in the vicinity of cytoplasmic membranes. The results indicate that in such an environment, adenosine aminohydrolase would be expected to be less efficient a catalyst, but equally susceptible to product inhibition, as compared to media of dielectric constant approaching that of water.

Adenosine Deaminase↗
PubMedDate not supplied

Circannual variation in human erythrocyte adenosine aminohydrolase.

In serially independent samples of blood from apparently healthy subjects controlled as to clock-hour of blood withdrawal but not as to any circannual changes in circadian state, human erythrocyte adenosine aminohydrolase undergoes a statistically significant circannual rhythm, which may or may not be aliased. This rhythm is also demonstrated in patients with a variety of neoplastic diseases and it occurs around a statistically significantly lower mesor in patients with a variety of malignant tumors investigated.

Adenosine Deaminase↗