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Biomedical subjects

A W Nicholas

Publications and source records attributed to A W Nicholas.

17 recordsLinked to original sources
PubMed1993

Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs.

A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents. Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures. In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S configuration results in compounds with enhanced T-I inhibition. Compounds in the 20RS configuration were less active in vitro and in vivo and those in the 20R configuration were inactive. Compounds with 10,11-methylenedioxy substitution on ring A displayed a marked increase in potency in the T-I inhibition assay. The activities of some of the analogs as determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-I inhibition. A number of water-soluble analogs such as 20-glycinate esters, 9-glycinamides, or hydrolyzed lactone salts were prepared and tested in in vitro and in vivo assays. In general, these compounds were less active than CPT both in terms of T-I inhibition and life prolongation in the L-1210 assay. However, certain 20-glycinate esters showed good in vivo activity after iv administration.

Animals↗
PubMed1990

Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogues of camptothecin.

The total synthesis of the pentacyclic camptothecin analogues 3 and 4 in 11 steps from p-tolualdehyde is described. The overall shape of compound 3 is the same as that of potent, naturally occurring camptothecin (1a). Despite the near spatial identity of 3 and 1b (racemic, (20RS)-camptothecin) from a three-dimensional standpoint, the 9KB and 9PS cytotoxicity assays indicate at least a 40-60-fold decrease in activity of 3 compared to that of 1b, and the isomer 4 was inactive. Similarly, studies of the inhibition of topoisomerase I activity indicated only slight activity for 3 and no activity for 4. It is evident that the pyridone ring D is essential for antitumor activity. Three E ring modified analogues of camptothecin, 2d-f, are described in which the net change is replacement of O by N in ring E. Compared to (20S)-camptothecin (1a) or (20RS)-camptothecin (1b), the ring E modified analogues 2d-f display little or no cytotoxic activity, greatly reduced effect on the inhibition of topoisomerase I, and total loss of life prolongation in the in vivo L-1210 mouse leukemia assay, indicative of the highly restricted structural and electronic requirements of ring E for biological activity in camptothecin.

Animals↗
PubMed1989

DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts.

Drug development is needed to improve chemotherapy of patients with locally advanced or metastatic colon carcinoma, who otherwise have an unfavorable prognosis. DNA topoisomerase I, a nuclear enzyme important for solving topological problems arising during DNA replication and for other cellular functions, has been identified as a principal target of a plant alkaloid 20(S)-camptothecin. Significantly increased concentrations of this enzyme, compared to that in normal colonic mucosa, were found in advanced stages of human colon adenocarcinoma and in xenografts of colon cancer carried by immunodeficient mice. Several synthetic analogs of camptothecin, selected by tests with the purified enzyme and tissue-culture screens, were evaluated in the xenograft model. Unlike other anticancer drugs tested, 20(RS)-9-amino-camptothecin (9-AC) induced disease-free remissions. The overall drug toxicity was low and allowed for repeated courses of treatment.

Adenocarcinoma↗
PubMed1989

DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues.

20(S)-Camptothecin, the 20(S)-camptothecin sodium salt, and 12 analogues with substituents on the A ring differ widely in their effectiveness in the treatment of murine L1210 lymphoblastic leukemia in vivo. The drugs were screened in the following systems: System 1, the cleavage of DNA in the presence of purified topoisomerase I; System 2, drug-induced trapping of topoisomerase I in a covalent complex with DNA; and System 3, the induction of protein-associated DNA breaks in drug-treated L1210 leukemia cells. 9-Amino-20(S), 10-amino-20(RS), and 10,11-methylenedioxy-20(RS), drugs effective against murine L1210 leukemia in vivo, stabilize topoisomerase I-DNA cleavable complexes in a purified system and in cultured L1210 cells. Other analogues, inactive against L1210 leukemia in vivo, were totally ineffective in topoisomerase I-directed screens. The rest of the analogues were intermediate in terms of their antitumor and topoisomerase I-directed activities. The study shows that the drug-induced accumulation of enzyme-DNA cleavable complexes is directly proportional to drug cytotoxicity and antitumor activity.

Animals↗
PubMed1987

Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations.

Nineteen racemic ring A substituted analogues of the antitumor agent 20(S)-camptothecin were prepared by total synthesis and evaluated for in vitro cytotoxic activity against KB cell culture and in vivo antileukemic activity against L1210. These compounds bore a wide variety of substituents at C11 designed to confer upon the ring system a broad range of combinations of electronic, steric, and lipophilic effects. A few C10-substituted derivatives as well as C10,C11-disubstituted analogues prepared as part of a concurrent study have also been included for general comparison. With the notable exception of the cyano derivative, the 11-substituted compounds displayed only modest in vitro and in vivo activities, and there was a remarkable insensitivity toward the nature of the substituent. In contrast, the 9- and 10-substituted compounds exhibited a considerably higher level of dose potency and activity both in vitro and in vivo.

Animals↗
PubMed1987

Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-ethyl-5'-hydroxy-2'H,5'H,6'H-6'-oxopyrano[3' ,4'- f]delta 6,8-tetrahydro-indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin.

The resolution of the tricyclic ketone (3a + 3b) by the separation of diastereomeric adducts 4a and 4c of the precursor ketal 5 is described. The regenerated enantiomers 3a and 3b of 100% optical purity represent the key intermediates from which 20(R)-camptothecin (1a) and 20(S)-camptothecin (1b), respectively, have been prepared. The 20R analogue 1a was 10-100 times less active than the natural 20(S)-camptothecin (1b) in 9KB and 9PS cytotoxicity assays and almost inactive in in vivo L-1210 leukemia tests as compared to the highly potent and active natural compound 1b.

Camptothecin↗
PubMed1986

Plant antitumor agents. 22. Isolation of 11-hydroxycamptothecin from Camptotheca acuminata Decne: total synthesis and biological activity.

The antitumor alkaloid 11-hydroxy-(20S)-camptothecin was isolated from the woody tissue of Camptotheca acuminata. Structural proof derived from comparison with racemic 4 prepared by total synthesis. Antitumor activity of racemic 4 in L1210 leukemia in mice was considerably greater than that of natural (20S)-camptothecin and its sodium salt. There was also no toxic effect observed even at relatively high doses.

Animals↗
PubMed1986

Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues.

Eight optically active and nine racemic ring A modified analogues of 20(S)-camptothecin were prepared and evaluated for antitumor activity in the L-1210 leukemia system. The ring A mono- and disubstituted analogues displayed a wide variance in activity and potency. It was found that monosubstitution by NH2 or OH at positions 9, 10, or 11 yielded compounds with activity much higher than the parent compound, camptothecin, whereas substitution at position 12 greatly reduced activity. In general, disubstitution in ring A greatly reduced antileukemic activity. Replacement of ring A by heterocyclic rings (thiophene or pyridine) leads to analogues with only moderate activity.

Animals↗
PubMed1984

Novel cytotoxic and antitumor agents. IV. Withaferin A: relation of its structure to the in vitro cytotoxic effects on P388 cells.

In vitro effects of withaferin A and its 9 new derivatives on P388 cells have been studied. The cytotoxicity was calculated from the utilization of precursors in protein and nucleic acid (NA) synthesis and from capacity to suppress cell proliferation. The most potent agents proved to be 4-dehydrowithaferin A and withaferin A diacetate exhibited an equal inhibitory effect on thymidine, uridine, and L-valine incorporation. They stopped cell proliferation and, at the same time, killed the cells. Cytotoxicity was found to be due to a double bond at position C2-3, by dissociating this bond the cytotoxicity markedly decreased in all derivatives. A dissociation of the double bond at C24-25 or a removal of OH group from C27 did not cause any significant changes in the biological effects of the derivatives. An addition of a carbonyl group at C4 increased the effects of the agent. An addition of OH groups to the molecule of withaferin A resulted chiefly in a qualitative change in the action of derivatives manifested by a significant decrease in L-valine inhibition. As withaferin A promptly reacted with L-cysteine, it was presumed that one of the possible target sites in the cell might be the SH groups of enzymes which react with the lactone and epoxide groups of the agent.

Animals↗
PubMed1983

Synthesis of mixed-acid phosphatidylcholines and high pressure liquid chromatographic analysis of isomeric lysophosphatidylcholines.

A new method for the synthesis of mixed-chain phosphatidylcholines is reported. Silver ion catalyzed acylation of lysophosphatidylcholines by 2-thiopyridyl esters occurs rapidly (10 min) at room temperature in organic solvents. Yields of isomerically pure mixed-chain phosphatidylcholines (greater than 98% isomeric purity) are generally greater than 80%. The reaction proceeds with only 1.5- to 2-fold excess of thiopyridyl ester, thus offering some advantages over existing procedures when precious acylating agents are used. The major disadvantage of the procedure is its sensitivity to water. Phosphatidylcholines having hydroxy fatty acyl groups are prepared by protection of the hydroxyl as the levulinate ester, conversion to the 2-thiopyridyl ester, acylation, and removal of the levulinate with hydrazine. For purification of lysophosphatidylcholines, a reverse-phase high pressure liquid chromatographic method for separation of 1-acylglycerophosphocholines from 2-acylglycerophosphocholines was developed.

Chromatography, High Pressure Liquid↗
PubMed1979

Transitional myeloproliferative disorder.

Eleven patients have been observed with clinical features of both polycythaemia vera and myelofibrosis. Detailed follow-up and repeated haematological and isotopic investigations, including the assessment of erythropoietic distribution by 52Fe scanning, over a 10 year period, have indicated that patients who initially present with this syndrome may remain in a steady state for several years and that this transitional syndrome does not necessarily imply an active or irreversible transformation into classical myelofibrosis. Therapy with iron, folic acid, alkylating agents, splenectomy or splenic irradiation may reduce the extramedullary component of myeloproliferation and allow occasional patients to revert to more classical polycythaemia vera. Radioactive phosphorus (32P) therapy may be inappropriate in polycythaemic patients with dominant extramedullary erythropoiesis, as this form of therapy has a preferential medullary action and may selectively encourage extramedullary myeloproliferation.

Adult↗
PubMed1978

Microbial transformations of natural antitumor agents. 7. 14-alpha-Hydroxylation of withaferin-A by Cunninghamella elegans (NRRL 1393).

Microbial transformation experiments were conducted with the steroidlactone, withaferin-A (1a). Cunninghamella elegans (NRRL 1393) converts withaferin-A into two major metabolites, one of which has been indentified as 14alpha-hydroxywithaferin-A (1b). The metabolite is obtained in 37% yield, and its structure was determined on the basis of pmr and mass spectral evidence. The metabolite has the same level of antitumor activity as withaferin-A against the Sarcoma-180 tumor test system in mice.

Animals↗
PubMed1978

Hepatic iron clearance from serum in treated hemochromatosis.

Hepatic iron uptake from transferrin has been studied in 7 patients with treated hemochromatosis. When compared with a control group with similar serum iron and transferrin saturation the hemochromatotics had a significantly higher 4-hr iron uptake value. Uptake in the precirrhotic and cirrhotic hemochromatotics was not significantly different, suggesting the existence of a cellular abnormality of hepatic iron metabolism in this disease. The results provide an explanation for the development of siderosis in some patients with idiopathic hemochromatosis and a normal serum iron concentration.

Adult↗
PubMedDate not supplied

Two-dimensional diffraction scanning of normal and cancerous human hepatic tissue in vitro.

A technique and associated equipment are described which investigate the acoustic signals backscattered from small tissue volumes and interrogated over a solid angle of transmitter/receiver positions. This two-dimensional diffraction technique produces acoustic scatter maps termed, by us "interferograms", which are analysed to determine their usefulness in discriminating between normal, freshly excised liver tissue and cancerous tissue within the intact organ. The "interferograms" are collected at three different narrow-band frequencies and have been used in investigating 26 normal liver and 13 liver tumour samples. The preliminary results indicate that this novel technique has a 97% success in discriminating normal liver from tumour, compared to an 87% success achieved by two observers when scoring conventional sector B-scan images of the same tissue regions.

Humans↗