Katherine L. Hamelehle

In vivo and in vitro anticancer activity of the structurally novel and highly potent antibiotic CI-940 and its hydroxy analog (PD 114,721)

SummaryCI-940, PD 114,721, and PD 118,607 are structurally novel antibiotics, which were isolated from fermentation beers of a previously unknown actinomycete. They are highly lipophilic acids characterized by unsaturated lactone and branched, polyunsaturated aliphatic sidechain moieties. All three agents demonstrated significant cytotoxic activity in vitro against a number of human and mouse tumour lines which encompassed a wide range of tissue types. CI-940 retained full activity in vitro against lines of P388 leukemia that are resistant to Adriamycin, amsacrine, and mitoxantrone. Activity was confirmed for both CI-940 and PD 114,721 against a number of murine experimental tumor systems in vivo, which included the P388 and L1210 leukemias and also B16 melanoma, Ridgway osteogenic and M5076 sarcomas, and mammary adenocarcinoma 16/C. PD 118,607 was also highly active against B16 melanoma. All three agents demonstrated anticancer activity at very low dosages compared with current clinically useful anticancer agents. No significant activity was seen against the MX-1 human mammary xenograft or pancreas 02 tumor models. The primary target for host toxicity of CI-940 and PD 114,721 appeared to be gastrointestinal in nature. Neither CI-940 nor PD 114,721 caused delayed lethality when given either IP or IV. In schedule studies, the toxicities of both CI-940 and PD 114,721 were moderately dependent on the regimen used, with total maximum tolerated dosages for intermittent (q4dx2), daily (qdx5), and divided daily (q4hx3, qdx5) dosing schedules of 1, 0.25, and 0.12 mg/kg, respectively.CI-940 is being developed for clinical trial on the basis of its potent activity against seven different tumor models, its novel structure, and its apparently novel mechanism of action.

Activity of the pyrazoloacridines against multidrug-resistant tumor cells

SummaryA series of 2-aminoalkyl-5-nitropyrazolo [3,4,5-kl]acridines (pyrazoloacridines) were tested in vitro against a panel of multidrug-resistant cell lines comprising Adriamycin-resistant P388 leukemia, B16 melanoma, and mammary adenocarcinoma 16c. This new class of anticancer agents, particularly the 9-substituted methoxy derivatives, exhibited significant activity against all of the lines tested. The degree of cross-resistance to these compounds ranged from zero to 8-fold in the 138-fold Adriamycin-resistant P388/ADR line and was greatly diminished in the B16/ADR and 16c/ADR lines. Selected pyrazoloacridines were subsequently tested in vivo against B16 and B16/ADR cells established as solid tumors from the tissue culture line and shown to retain a significant degree of Adriamycin resistance. Whereas the B16/ADR line exhibited 2 logs less net tumor-cell kill than the B16 parent in response to Adriamycin treatment, the resistant tumor was completely sensitive to the pyrazoloacridines tested and proved in some experiments to be collaterally sensitive. The favorable activity of the pyrazoloacridines against these Adriamycin-resistant tumor lines points to the potential efficacy of these compounds against multidrug-resistant tumors encountered clinically.

Inhibitors of Acyl-CoA:Cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: Synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates

Sulfoacetic acid, phosphoramidate, and phosphoramide analogs of the ACAT inhibitors, CI-999 and CI-1011 were synthesized. The structure-activity relationships of these compounds as ACAT inhibitors are described.

A series of conformationally and sterically constrained analogs of N-phenyl-N′-aralkylurea ACAT inhibitors☆

Abstract A series of conformationally and sterically constrained analogs of N-phenyl-N′-aralkylureas has been synthesized and evaluated as potential ACAT inhibitors. Most of these analogs are potent inhibitors of ACAT in vitro and lower plasma cholesterol in an acute in vivo model of hypercholesterolemia.

Imidazolidinones and pyrazolones as novel ACAT inhibitors: Chemistry and biological activity

Abstract Our continued interest in inhibitors of acyl-coenzyme A:cholesterol acyltransferase (ACAT) has led us to study a series of imidazolidinones (I) and a series of pyrazolones (II), two systems structurally distinct from our other reported series. The synthesis and biological activity of I and II are reported.

Inhibitors of acyl-CoA:cholesterol acyltransferase: novel trisubstituted ureas as hypocholesterolemic agents

Our continued interest in developing novel, potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, and our discovery of several active series of disubstituted urea ACAT inhibitors, have led us to investigate a series of trisubstituted ureas that are structural hybrids of our disubstituted series and of a trisubstituted urea ACAT inhibitor series disclosed by scientists at Lederle. This investigation has led to the discovery of novel trisubstituted ureas, several of which inhibit ACAT in the nanomolar range and effectively lower total plasma cholesterol when administered as a diet admixture in an acute model of hypercholesterolemia in rats. One analogue (35) also lowered total cholesterol as efficaciously as CL 277,082 in our chronic hypercholesterolemic rat model. The most notable finding of this study is that the SAR of the trisubstituted ureas diverges from that seen in our previously disclosed disubstituted urea series. This series showed optimal activity with 2,4-difluoro and 2,4,6-trifluoro substitution on the urea N-phenyl, whereas the disubstituted series showed optimal activity with bulky 2,6-disubstitution on the phenyl ring.

Inhibitors of acyl-coa:cholesterol acyltransferase (ACAT). 15. sulfonylurea inhibitors with excellent hypocholesterolemic activity in vivo.

Abstract A series of sulfonylureas were prepared and tested for the ability to inhibit the enzyme acyl-CoA: cholesterol acyltransferase (ACAT) in vitro and lower plasma cholesterol in cholesterol-fed rats in vivo. Although compounds from this series were generally weak inhibitors of ACAT in vitro, several displayed excellent hypocholesterolemic activity in vivo.

Inhibitors of Acyl-CoA:Cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents 14. synthesis and structure-activity relationships of a novel series of sulfonamide tetrazoles

Abstract The syntheses and biological activities of a series of novel sulfonamide tetrazole derivatives are reported. The ability of these compounds to inhibit ACAT is described. Such agents may decrease the absorption of dietary cholesterol in the intestine and/or the secretion of VLDL by the liver and therefore provide a therapy for the treatment of hypercholesterolemia and atherosclerosis in man.