Doxsaliform: A Novel N-Mannich Base Prodrug of a Doxorubicin Formaldehyde Conjugate

Cogan, Peter S; Fowler, Catherine R; Post, Glen C.; Koch, Tad H.

doi:10.2174/1570180043399000

Cited by 17 publications

(44 citation statements)

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“…5 The initial distribution of 10 was predominantly cytosolic, with noticeable accumulation in several focal points throughout both PC3/AR ( Figure 5a) and PC3/neo (Figure 5b) cells. Similar localization was observed for 1b upon initial treatment with a 500 nM solution of the prodrug (not shown).…”

Section: Resultsmentioning

confidence: 96%

“…We have found that acyloxymethylation of the phenolic moiety of salicylamide leads to a stable N-Mannich base product upon reaction with doxorubicin. 5 Preparation of this derivative allows for study of the intact prodrug without concern for the activity of 6a, which is released upon partial hydrolysis of 9 and can be expected to compete for AR binding. Competitive binding of both 9 and 10 has been confirmed using the cell free assay.…”

Section: Resultsmentioning

confidence: 99%

“…The syntheses of compounds 1b, 4, 5, 6a, 7, 8, and 9 have been previously reported, as have the methodologies employed in the competitive binding and IC50 measurements of compounds 9 and 10. 5,15 All tissue culture materials were obtained from Gibco Life Technologies (Grand Island, NY) unless otherwise noted. PC3/ AR and PC3/neo cells were a gift from Dr. Kerry L. Burnstein (University of Miami, FL).…”

Section: Methodsmentioning

confidence: 99%

“…Herein is described the intracellular response of the AR-GFP receptor in PC3 cells upon exposure to a series of AR targeted derivatives of salicylamide, the amide moiety of the N-Mannich base doxsaliform. Also described is (4)(5)(6)(7)(8)(9)(10), and the highly toxic, prodrug, doxorubicin-formaldehyde conjugate, doxoform. the action of the doxorubicin N-Mannich base product formed from the most effective targeting compound of the tested series.…”

Section: Introductionmentioning

confidence: 99%

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Studies of Targeting and Intracellular Trafficking of an Anti-Androgen Doxorubicin−Formaldehyde Conjugate in PC-3 Prostate Cancer Cells Bearing Androgen Receptor-GFP Chimera

Cogan

Koch

2004

J. Med. Chem.

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The synthesis of a doxorubicin-formaldehyde conjugate bound to the nonsteroidal anti-androgen cyanonilutamide, via a cleavable tether, and binding of the construct to cell free androgen receptor (AR) as a function of tether design were previously reported. Cyanonilutamide bearing a linear alkyne tether bound to the AR better than other designs. Fluorescence microscopy studies of binding of the lead targeted drug, as well as various tethered cyanonilutamides, to the AR and subsequent trafficking of the resulting AR complex in live PC3 prostate cancer cells transfected with AR-green fluorescent protein (GFP) chimera are now described. Cyanonilutamide and cyanonilutamide bonded to a linear alkyne tether caused translocation of AR-GFP to the nucleus. In general, the ability of tethered cyanonilutamides to cause translocation paralleled their binding affinity for the AR. However, a noncleavable form of the lead cyanonilutamide-doxorubicin-formaldehyde conjugate bound to AR-GFP but the resulting complex did not translocate to the nucleus. Binding was apparent from the drugs inhibition of Mibolerone-induced translocation. Direct observation of anthraquinone fluorescence of targeted drug in PC3 cells showed initial cytosolic localization, independent of AR expression, with predominant nuclear localization after sufficient time for release of drug from the targeting moiety. The results indicate that doxorubicin-formaldehyde conjugate bonded to cyanonilutamide via a cleavable linear tether enters PC3 cells, resides in cytosol, binds to the AR if present, and ultimately releases doxorubicin or a doxorubicin derivative to the nucleus.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Studies of Targeting and Intracellular Trafficking of an Anti-Androgen Doxorubicin−Formaldehyde Conjugate in PC-3 Prostate Cancer Cells Bearing Androgen Receptor-GFP Chimera

Cogan

Koch

2004

J. Med. Chem.

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“…6, 2017 tool to improve the biological activity of many drugs as tetracyclines and doxorubicin. 18,19 Recent literature has shown phenolic Mannich bases derived from chalcones analogues to have remarkable cytotoxic potencies towards cancer cell lines. [20][21][22][23][24] However, the exact mechanism by which chalcone compounds and derivatives exert their cytotoxic effects in cancer cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Study of Reactions of Two Mannich Bases Derived of 4’-Hydroxychalcones with Glutathione by RP‑TLC, RP‑HPLC and RP‑HPLC‑ESI‑MS Analysis

Bernardes¹,

Pérez²,

Mayer³

et al. 2016

J. Braz. Chem. Soc.

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4'-Hydroxychalcones have been reported to possess several beneficial biological effects. Several lines of evidence accumulated to demonstrate increased biological activities of the Mannich base derivatives of the parent 4'-hydroxychalcones. Bioactivities of chalcones and related α,β-unsaturated ketones are frequently associated with their reactivity with cellular thiols, such as GSH. For comparison of GSH reactivity, two bis Mannich bases of two 4'-hydroxychalcones were synthesized and reacted with GSH under non-cellular conditions. Reversed-phase thin layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC) analysis showed formation of two polar products which structures were confirmed by RP-HPLC-ESI-MS (RP-HPLC-electrospray ionization mass spectrometry) as 1:1 chalcone-GSH adducts in each case. At pH values below 8.0, the two bis Mannich bases showed higher GSH reactivity than two 4'-hydroxychalcones. Influence of the nature of the amino groups, the ring-B substituents and pH of the medium on reactivity was also investigated. The findings could serve as useful structure-activity information for subsequent molecular modification of thiol-reactive 4'-hydroxychalcones.

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Anthracycline–Formaldehyde Conjugates and Their Targeted Prodrugs

Koch

Barthel

Kalet

et al. 2007

Topics in Current Chemistry

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The sequence of research leading to a proposal for anthracycline cross-linking of DNA is presented.The clinical anthracycline antitumor drugs are anthraquinones, and as such are redox active. Their redoxchemistry leads to induction of oxidative stress and drug metabolites. An intermediate in reductive glycosidiccleavage is a quinone methide, once proposed as an alkylating agent of DNA. Subsequent research nowimplicates formaldehyde as a mediator of anthracycline-DNA cross-linking. The cross-link at 5'-GC-3'sites consists of a covalent linkage from the amino group of the anthracycline to the 2-amino groupof the G-base through a methylene from formaldehyde, hydrogen bonding from the 9-OH to the G-base onthe opposing strand, and hydrophobic interactions through intercalation of the anthraquinone. The combinationof these interactions has been described as a virtual cross-linkof DNA. The origin of the formaldehyde in vivo remains a mystery. In vitro, doxorubicin reacts withformaldehyde to give firstly a monomeric oxazolidine, doxazolidine, and secondly a dimeric oxazolidine,doxoform. Doxorubicin reacts with formaldehyde in the presence of salicylamide to give the N-Mannich baseconjugate, doxsaliform. Doxsaliform is several fold more active in tumor cell growth inhibition than doxorubicin,but doxazolidine and doxoform are orders of magnitude more active than doxorubicin. Exploratory researchon the potential for doxsaliform and doxazolidine as targeted cytotoxins is presented. A promisinglead design is pentyl PABC-Doxaz, targeted to a carboxylesterase enzyme overexpressed in liver cancercells and/or colon cancer cells.

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Doxsaliform: A Novel N-Mannich Base Prodrug of a Doxorubicin Formaldehyde Conjugate

Cited by 17 publications

References 0 publications

Studies of Targeting and Intracellular Trafficking of an Anti-Androgen Doxorubicin−Formaldehyde Conjugate in PC-3 Prostate Cancer Cells Bearing Androgen Receptor-GFP Chimera

Studies of Targeting and Intracellular Trafficking of an Anti-Androgen Doxorubicin−Formaldehyde Conjugate in PC-3 Prostate Cancer Cells Bearing Androgen Receptor-GFP Chimera

Study of Reactions of Two Mannich Bases Derived of 4’-Hydroxychalcones with Glutathione by RP‑TLC, RP‑HPLC and RP‑HPLC‑ESI‑MS Analysis

Anthracycline–Formaldehyde Conjugates and Their Targeted Prodrugs

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