Epidoxoform: a hydrolytically more stable anthracycline-formaldehyde conjugate toxic to resistant tumor cells

Journal of Medicinal Chemistry
D J TaatjesT H Koch

Abstract

The recent discovery that the formaldehyde conjugates of doxorubicin and daunorubicin, Doxoform and Daunoform, are cytotoxic to resistant human breast cancer cells prompted the search for hydrolytically more stable anthracycline-formaldehyde conjugates. Doxoform and Daunoform consist of two molecules of the parent drug bound together with three methylene groups, two forming oxazolidine rings and one binding the oxazolidines together at their 3'-amino nitrogens. The 4'-epimer of doxorubicin, epidoxorubicin, reacts with formaldehyde at its amino alcohol functionality to produce a conjugate, Epidoxoform, in 59% yield whose structure consists of two molecules of epidoxorubicin bound together with three methylene groups in a 1, 6-diaza-4,9-dioxabicyclo[4.4.1]undecane ring system. The structure was established from spectroscopic data and is consistent with products from reaction of simpler vicinal trans-amino alcohols with formaldehyde. Epidoxoform hydrolyzes at pH 7.3 to an equilibrium mixture with dimeric and monomeric epidoxorubicin-formaldehyde conjugates without release of formaldehyde or epidoxorubicin. The hydrolysis follows the rate law (A if B) if C + D where A (Epidoxoform) is in rapid equilibrium with B, and B is in slow e...Continue Reading

References

Jan 11, 1995·Nucleic Acids Research·A van RosmalenD R Phillips
Aug 1, 1997·Journal of Medicinal Chemistry·D J FenickT H Koch

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Citations

Dec 25, 2012·Cancer Chemotherapy and Pharmacology·Robert A ForrestSuzanne M Cutts
Jul 11, 2006·Journal of Cancer Research and Clinical Oncology·Dikla EngelAda Rephaeli
Mar 23, 2011·Biochemistry. Biokhimii︠a︡·V A Efimov, S V Fedyunin
Dec 22, 2004·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Azra RabbaniJuan Ausió
Apr 14, 2010·Bioorganicheskaia khimiia·V A EfimovO G Chakhmakhcheva
Apr 14, 2007·Molecular Cancer Therapeutics·Suzanne M CuttsDon R Phillips
Jan 1, 2008·Journal of Medicinal Chemistry·Dikla EngelAda Rephaeli
Nov 24, 2005·Journal of Medicinal Chemistry·Glen C PostTad H Koch

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