Substituent Effects on Oxidation‐Induced Formation of Quinone Methides from Arylboronic Ester Precursors

Abstract

A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N(+)Me3Br(-)) have been synthesized. The substituent effects on their reactivity with H2O2 and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used to determine the reaction mechanism and QM formation, respectively. QMs were not generated during oxidative cleavage of the boronic esters but by subsequent transformation of the phenol products under physiological conditions. The oxidative deboronation is facilitated by electron-withdrawing substituents, such as aromatic F, NO2, or benzylic N(+)Me3Br(-), whereas electron-donating substituents or a better leaving group favor QM generation. Compounds containing an aromatic CH3 or OMe group, or a good leaving group (Br), efficiently generate QMs under physiological conditions. Finally, a quantitative relationship between the structure and activity has been established for the arylboronic esters by using a Hammett plot. The reactivity of the arylboronic acids/esters and the inhibition or facilitation of QM formation can now be predictably adjusted. This adjustment is important as some applications may benefit and others may be limited by QM generation.

Photochemical Generation of Benzyl Cations That Selectively Cross-Link Guanine and Cytosine in DNA

“…Our LC–MS/MS results revealed the presence of dinucleosides in the digestion mixture, where 4b is conjugated with a dG and a dC (Scheme 2 and SI, Figure S29 and Scheme S5) (note: the boronate ester 4b was hydrolyzed to the boronic acid derivative 4b* during cross-linking and/or purification process) (SI, Figure S30). 45 The MS/MS for the [M + H] + ion of dG- 4b *-dC revealed a peak eluting at 26.4 min in the selected-ion chromatogram (SIC) for the m / z 671.3 ( 11 ) → 555.2 ( 12 ) transition, which monitors the neutral loss of a 2-deoxyribose. Fragment ion of m / z 439.0 ( 13 ) was also found in the MS/MS due to the neutral loss of the second 2-deoxyribose.…”

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

“…These species are typically formed only transiently, and yet have found utility in the synthesis of natural products 35,36 , polymers 37 and cytotoxic agents 38 , as well as in functionalization of molecular surfaces 39 . QM formation and regeneration are exquisitely sensitive to electronic effects as evident from the five orders of magnitude separating rate constants for QMs differing by a single substituent 31,40 . Although the reversibility of QM reaction may complicate detection of their adducts formed by xenobiotic metabolism of certain drugs and food additives [41][42][43] , the reversibility has allowed for the construction of target-inducible and site-selective alkylating agents [44][45][46] .…”

Novel delivery approaches for cancer therapeutics

“…Peng and group developed H 2 O 2 activated aromatic nitrogen mustard based prodrugs where the DNA alkylating agent is connected to a H 2 O 2 responsive trigger by an electron withdrawing group. Such an approach of ROS-activation provided better specificity and lower toxicity [120, 159–161]. A melphalan derived prodrug, melflufen (J1) which releases the parent drug by hydrolytic cleavage of the peptide bond by aminopeptidase N (APN) thereby eliciting anti-anigiogenic effects [162].…”