Synthetic Enantiopure Aziridinomitosenes:  Preparation, Reactivity, and DNA Alkylation Studies

Vedejs, E.; Naidu, B. Narasimhulu; Klapars, Artis; Warner, Don L.; Li, Ven Shun; Na, Younghwa; Kohn, Harold

doi:10.1021/ja030452m

Cited by 52 publications

(44 citation statements)

References 76 publications

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“…The oil was purified by MPLC column chromatography (cyclohexane:ethyl acetate 8/2) to give 0.330 g of 1 (85.5%) as a white solid. 33 8, 122.7, 126.6, 127.0, 131.3, 131.6, 134.7, 138.1, 158.5, 192.4 4,63.6,109.4,119.0,126.5,127.7,128.0,128.6,129.2,130.2 134.3,155.1. Anal.…”

Section: Methodsmentioning

confidence: 99%

“…13 C NMR (CDCl 3 ): 53. 4,63.5,66.6,109.4,118.3,126.3,128.0,128.2,128.3,129.4,131.4 134.0,153.9. Anal.…”

Section: Methodsmentioning

confidence: 99%

“…Compound 4b exhibited a high SI (SI 33) only on HT-29 cells, but poor on the A549 cell line (SI 9). The other binolams 4a and 4h exhibited higher EC 50 paralleled by higher CC 50 ; however, SI remained in general low (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). PS (4,5′,8-trimethylpsoralen), used as a control, in these conditions displayed lower SI than the analyzed compounds.…”

Section: Photocytotoxic and Cytotoxic Effects Of Binol-amino Acidmentioning

confidence: 96%

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Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents

et al. 2010

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A one-step protecting-group-free synthesis of both 6-hydroxy-naphthalene-2-carbaldehyde and the bifunctional binaphthalenyl derivative afforded 6-hydroxymethylnaphthalen-2-ol, 6-methylaminomethyl-naphthalen-2-ol, [(2-hydroxy-3-naphthyl)methyl]trimethyl ammonium iodide, and a small library of bifunctional binol analogues in good yields. Irradiation of naphthol quaternary ammonium salt and binol-derivatives (X = OH, NHR, NMe(3)(+), OCOCH(3), and L-proline) at 310 and 360 nm resulted in the photogeneration of the 2,6-naphthoquinone-6-methide (NQM) and binol quinone methide analogues (BQMs) by a water-mediated excited-state proton transfer (ESPT). The hydration, the mono- and bis-alkylation reactions of morpholine and 2-ethanethiol, as N and S prototype nucleophiles, by the transient NQM (λ(max) 310, 330 nm) and BQMs (λ(max) 360 nm) were investigated in water by product distribution analysis and laser flash photolysis (LFP). Both the photogeneration and the reactivity of NQM and BQMs exhibited striking differences. BQMs were at least 2 orders of magnitude more reactive than NQM, and they were generated much more efficiently from a greater variety of photoprecursors including the hydroxymethyl, quaternary ammonium salt and several binol-amino acids. On the contrary, the only efficient precursor of NQM was the quaternary ammonium salt. All water-soluble BQM precursors were further investigated for their ability to alkylate and cross-link plasmid DNA and oligonucleotides by gel electrophoresis: the BQMs were more efficient than the isomeric o-BQM (binol quinone methide analogue of 2,3-naphthoquinone-3-methide). Sequence analysis by gel electrophoresis, HPLC, and MS showed that the alkylation occurred at purines, with a preference for guanine. In particular, a BQM was able to alkylate N7 of guanines resulting in depurination at the oligonucleotide level, and ribose loss at the nucleotide level. The photoreactivity of BQM precursors translated into photocytotoxic and cytotoxic effects on two human cancer cell lines: in particular, one compound showed promising selectivity index on both cell lines.

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Section: Methodsmentioning

confidence: 99%

“…13 C NMR (CDCl 3 ): 53. 4,63.5,66.6,109.4,118.3,126.3,128.0,128.2,128.3,129.4,131.4 134.0,153.9. Anal.…”

Section: Methodsmentioning

confidence: 99%

Section: Photocytotoxic and Cytotoxic Effects Of Binol-amino Acidmentioning

confidence: 96%

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Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents

et al. 2010

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“…This coupling is small for a cis aziridine, but it is consistent with the spectra of other aziridinomitosenes. 18–20 Coalescence into a single pair of aziridine methine signals at 4.04 and 3.60 ppm was observed upon warming the sample to ca. 45 °C.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, an alternative method for carbamate installation using the milder FmocNCO reagent was investigated. 18,31 Initially, 33 was treated with freshly prepared FmocNCO/Et 3 N to give a crude product having characteristic C(10) methylene signals near 5 ppm, suggesting formation of 35 . Attempts to remove the Fmoc group from the presumed 35 using previously optimized conditions (Et 3 N/CH 3 CN) resulted in significant decomposition.…”

Section: Resultsmentioning

confidence: 99%

Reactivity of Aziridinomitosene Derivatives Related to FK317 in the Presence of Protic Nucleophiles

Wiedner

Vedejs

2011

J. Org. Chem.

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The syntheses and reactivity of N-TBDPS and N-trityl protected derivatives of an aziridinomitosene corresponding to FK317 are described. New reactivity patterns were observed for these highly sensitive and functionally dense heterocycles under mild nucleophilic conditions approaching the threshold for degradation. Thus, the silyl or trityl protected aziridinomitosene reacted with Cs2CO3/CD3OD to give isomeric products where substitution occurred at C(10) and C(9a) (mitomycin numbering) providing a CD3 ether and a CD3 hemiaminal respectively. These findings show that heterolysis at C(10) is faster than at aziridine C(1), in contrast to the behavior of typical aziridinomitosenes in the mitomycin series. The labile N-TBDPS hemiaminal and the more stable N-trityl hemiaminal resemble the mitomycin K substitution pattern. A reagent consisting of CsF in CF3CH2OH/CH3CN desilylated a simple N-TBDPS aziridine, but caused nucleophilic cleavage at C(1) as well as C(10) without cleavage of the N-TBPDS group in the fully functionalized penultimate aziridinomitosene. The high reactivity of the C(10) carbamate with nucleophiles precludes the use of deprotection methodology that requires N-protonation for fully functionalized aziridinomitosenes in the FK317 series.

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Methanesulfonic Acid

Subramanian¹,

Hanack²,

Martı́nez³

et al. 2007

Encyclopedia of Reagents for Organic Synthesis

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Synthetic Enantiopure Aziridinomitosenes: Preparation, Reactivity, and DNA Alkylation Studies

Cited by 52 publications

References 76 publications

Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents

Photogeneration and Reactivity of Naphthoquinone Methides as Purine Selective DNA Alkylating Agents

Reactivity of Aziridinomitosene Derivatives Related to FK317 in the Presence of Protic Nucleophiles

Methanesulfonic Acid

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