Synthesis and antimetastatic properties of stereoisomeric tricyclic bis(dioxopiperazine) analogs in a B16 melanoma model

Witiak, Donald T.; Trivedi, Bharat K.; Campolito, Laura B.; Zwilling, Bruce S.; Reiches, Nancy A.

doi:10.1021/jm00143a013

Cited by 12 publications

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“…Reaction of 350 mg (0.48 mmol) of 7 with sebacic acid monosodium salt (1.8 g) in 400 mL of acetone containing 3 mL of water at reflux for 14 h, followed by isolation and purification as before, afforded 16 (242 mg, 63%): mp 108-112 °C dec; Chemical, biochemical, and pharmacological properties of antitumor bis(dioxopiperazines) recently have been reviewed.2 Cyclic analogues 4-9 of 1 and 2 exhibited stereoselective effects in various tumor models. [3][4][5][6] In the solid state a cis "face to face" conformation of the dioxopiperazine rings were observed in antimetastatic racemic 2 and cis-5.7,8 However, such a conformation seems not to be essential for activity since tricyclic bis(dioxopiperazine) trans-6 exhibited antimetastatic properties in the B16-F10 melanoma model.5,9…”

Section: Methodsmentioning

confidence: 99%

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Adriamycin analogs. Rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives

Israel¹,

Potti²,

Seshadri³

1985

J. Med. Chem.

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N-(Trifluoroacetyl)adriamycin 14-valerate (AD 32), a novel DNA nonbinding analogue of adriamycin with superior experimental antitumor activity, has undergone extensive clinical trial, with documentation of antitumor activity and low toxicity in human subjects. However, poor water solubility necessitates that the drug be administered to patients by continuous intravenous infusion at high dilution in a surfactant-containing formulation, with steroid prophylaxis to protect against a chest pain syndrome associated with the vehicle. On the basis of pharmacologic considerations, the title compounds have been prepared as second-generation analogues of N-(trifluoroacetyl)adriamycin 14-valerate with improved aqueous solubility; use is made of the available carboxylic acid function to solubilize the products in dilute aqueous alkaline medium. Target compounds were made by treating N-(trifluoroacetyl)-14-halodaunorubicin (bromo or iodo) with monosodium salts of dibasic acids (malonic, succinic, glutaric, adipic, pimelic, azelaic, sebacic) in aqueous acetone. All of the products showed significant in vivo antitumor activity against the murine P388 leukemia (ip tumor, ip treatment once daily on days 1, 2, 3, and 4); most compounds were superior to the +181% increase in life span afforded by adriamycin (optimal dose 3.0 mg/kg per day), one of two drugs used as positive controls for the assays. Several of the test compounds showed highly curative activity in this system, similar to N-(trifluoroacetyl)adriamycin 14-valerate, the other positive control agent. The hemiadipate product exhibited the most desirable properties of high antitumor efficacy (86% cure rate all P388 tumor-bearing animals through four levels of a 40-70 mg/kg dose-response range), aqueous solubility (60 mg/mL in pH 7.4 phosphate buffer), and solution stability (no decomposition at 4 degrees C, 0.5% hydrolysis at 27 degrees C, over 24 h at pH 7.4).

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Section: Methodsmentioning

confidence: 99%

“…; Lea and Febiger: Philadelphia, 1982; p 872. (5) (9) Chuang, L. F.; Kawahata, R. T.; Chuang, R. Y. FEBS. Lett.…”

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confidence: 99%

Adriamycin analogs. Rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives

Israel¹,

Potti²,

Seshadri³

1985

J. Med. Chem.

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“…but not ds-2, were active in this assay (180). To further define their geometrical requirements, the tetraazaperhydrophenanthrene diastereomers were synthesized (181).…”

Section: Scheme IVmentioning

confidence: 99%

Amelioration of Anthracycline-Induced Cardiotoxicity by Organic Chemicals

Witiak

Herman

1994

ACS Symposium Series

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The amelioration of anthracycline-induced cardiotoxicity by numerous organic chemicals is discussed. These include ion regulators, receptor site antagonists, and inhibitors of mediator release, energy regulators, enzyme inhibitors, membrane stabilizers, anthracycline uptake inhibitors, and inactivators, antioxidants and chelating materials, and various miscellaneous substances.Of these the bis(2,6-dioxopiperazine)s remain as the potentially most useful drugs.Recently published reviews (7,2) describe the various organic chemicals that serve to ameliorate acute and chronic anthracycline-induced toxicities at the cellular, animal, and clinical levels. In this review drugs are categorized according to the rationale proposed for their protective activity. Whereas major efforts have been directed towards decreasing myocardial concentrations of anthracyclines and their metabolites and the development of less cardiotoxic anthracyclines, this summary focuses upon the concurrent administration of substances that block anthracyclineinduced toxicities.As discussed in other chapters, anthracycline antitumor activity may be attributable to multiple mechanisms (1-3) such as (a) intercalation into DNA, (b) formation of ternary complexes with DNA topoisomerase n, and (c) radical-induced DNA strand breakage. The latter may involve anthracycline semiquinone radical-induced hydroxyl radical (HO*) formation, anthracycline semiquinone radical-induced superoxide anion radical (0 2 T )generation, and/or anthracycline-ferric ion complex catalyzed Fenton reactions (J).Anthracycline-induced cardiotoxicity also is a function of multiple mechanistic possibilities (1). Acute effects such as hypotension are inhibited by antagonists of neurotransmitters (4,5). Subacute toxicity is rare, is unrelated to cumulative anthracycline dose, and manifests itself within 4 weeks as pericarditis-myocarditis with pericardial effusion and ventricular dysfunction (6). Nucleolar segregation also

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“…Conformationally constrained bis(imides) (15)(16)(17)(18) (Fig. 3) prepared by Witiak and co-workers in the United States are related to ICRF-154 (5) and differ from 5 by only two hydrogen atoms in their molecular weight (29,30). Whereas 15 and 16, having a cisoid relationship between the imide functions, are diastereomerically related, 17 and 18 differed from 15 and 16 in the spatial orientation of the imide groups.…”

Section: Antimetastatic Propertiesmentioning

confidence: 99%

The evolution of a cardioprotective antimetastatic and antitumor drug: An international adventure

Nair¹,

Witiak²

1988

J. Chem. Educ.

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Synthesis and antimetastatic properties of stereoisomeric tricyclic bis(dioxopiperazine) analogs in a B16 melanoma model

Cited by 12 publications

References 0 publications

Adriamycin analogs. Rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives

Adriamycin analogs. Rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives

Amelioration of Anthracycline-Induced Cardiotoxicity by Organic Chemicals

The evolution of a cardioprotective antimetastatic and antitumor drug: An international adventure

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