Compounds with bridgehead nitrogen. Part 47. The reaction between trans-1-aminobenzocycloalkan-2-ols and formaldehyde

Barkworth, Peter M. R.; Crabb, Trevor A.; Robinson, Paul D.

doi:10.1039/p19830002807

Cited by 8 publications

(7 citation statements)

References 4 publications

(13 reference statements)

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“…Corresponding structures have been hypothesized or synthesized with dau. 17 In contrast, consistent with literature precedent, 18,19 the trans-amino alcohol found in epi does not result in stable oxazolidines upon reaction with formaldehyde but instead favors the formation of a bicyclic structure consisting of two epi units and three units of formaldehyde known as epiform (epiF, 10; Scheme 1, bottom). While epiF does display increased cytotoxicity over epi and overcomes resistance, it is far less potent than doxaz or doxF.…”

Section: ■ Introductionsupporting

confidence: 78%

Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde

et al. 2016

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Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA cross-linker. Contrary to current dogma, we show that both efficient DNA cross-linking and potent synergy in combination with formaldehyde correlate with the anthracycline's ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better cross-linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracycline prodrug design and development.

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Section: ■ Introductionsupporting

confidence: 78%

Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde

et al. 2016

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“…The methylenes of Epidoxoform and Doxoform appeared as a 4-proton AX pattern and a 2-proton singlet in both molecules. The primary difference is J AX which is 4 Hz in Doxoform, characteristic of a methylene in a fivemembered ring between two electronegative hetero- 16 Also of note is the observation of little change in the patterns for the protons at the 2′-and 3′-positions between epidoxorubicin and Epidoxoform. The same comparison of daunorubicin with Daunoform showed a factor of 2 change in one of the 2′-3′ coupling constants resulting from a dihedral angle change with formation of the fivemembered oxazolidine rings.…”

Section: Resultsmentioning

confidence: 98%

“…trans-2-Aminocycloheptanol forms a bis-oxazolidinylmethane analogous to doxorubicin; however, trans-2-aminocyclohexanol forms a 1,6-diaza-4,9-dioxabicyclo-[4.4.1]undecane ring system as shown in Scheme 2. [15][16][17] The chemistry appears to be controlled by the distance between the amino and alcohol functional groups.…”

Section: Introductionmentioning

confidence: 99%

Epidoxoform: A Hydrolytically More Stable Anthracycline−Formaldehyde Conjugate Toxic to Resistant Tumor Cells

1998

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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 equilibrium with C and D. The forward rate constant for A/B going to C+D gives a half-life of approximately 2 h at 37 degrees C. At equilibrium the mixture is stable for at least 2 days. At pH 6.0, hydrolysis proceeds with first-order kinetics to epidoxorubicin and formaldehyde with a half-life of 15 min at 37 degrees C. Epidoxoform and epidoxorubicin plus formaldehyde react with the self-complementary DNA octamer (GC)4 to yield five drug-DNA adducts which have structures analogous to the doxorubicin-DNA adducts from reaction of Doxoform with (GC)4. Epidoxoform is 3-fold more toxic to MCF-7 human breast cancer cells and greater than 120-fold more toxic to MCF-7/ADR resistant cells than epidoxorubicin. Epidoxoform in equilibrium with its hydrolysis products is greater than 25-fold more toxic to resistant cells with respect to epidoxorubicin.

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“…Racemic 9 and 10 were prepared by previously reported methods. 23,24 Enantiopure forms of 9 and 10 25 could be obtained by diastereomeric resolution using respectively (S)-naproxen and L-tartaric acid 25 as resolving agents.…”

Section: Trans-1-aminoindan-2-ol 21 Trans-2-mentioning

confidence: 99%

Design of Resolving Agents Based on Crystal Engineering

Kinbara

2005

Synlett

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As a result of systematic studies on the optical resolution of racemates via crystallization, we have found that in many cases, common characteristic hydrogen-bond networks were formed in the less-soluble diastereomeric salts or conglomerates. Design of resolving/derivatizing agents could be achieved on the basis of the concept of crystal engineering, by which molecules were designed to achieve stable hydrogen-bond networks with target racemates.

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Compounds with bridgehead nitrogen. Part 47. The reaction between trans-1-aminobenzocycloalkan-2-ols and formaldehyde

Cited by 8 publications

References 4 publications

Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde

Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde

Epidoxoform: A Hydrolytically More Stable Anthracycline−Formaldehyde Conjugate Toxic to Resistant Tumor Cells

Design of Resolving Agents Based on Crystal Engineering

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