Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids

Abstract

Higher-ordered structure motifs of nucleic acids, such as the G-quadruplex (G-4), mismatched and bulge structures, are significant research targets because these structures are involved in genetic control and diseases. Selective alkylation of these higher-order structures is challenging due to the chemical instability of the alkylating agent and side-reactions with the single- or double-strand DNA and RNA. We now report the reactive OFF-ON type alkylating agents, vinyl-quinazolinone (VQ) precursors with a sulfoxide, thiophenyl or thiomethyl group for the OFF-ON control of the vinyl reactivity. The stable VQ precursors conjugated with aminoacridine, which bind to the G-4 DNA, selectively reacted with a T base on the G-4 DNA in contrast to the single- and double-strand DNA. Additionally, the VQ precursor reacted with the T or U base in the AP-site, G-4 RNA and T-T mismatch structures. These VQ precursors would be a new candidate for the T or U specific alkylation in the higher-ordered structures of nucleic acids.

Mechanisms of Multidrug Resistance in Cancer Chemotherapy

“…Depending on the mechanism of action, they can be divided into alkylating agents, antimetabolites, topoisomerase inhibitors, mitotic spindle inhibitors, and others (Figure 1) [7][8][9]. Alkylating agents include the oxazsaphosphorines (cyclophosphamide and ifosfamide); nitrogen mustards (busulfan, chlorambucil, and melphalan); hydrazine (temozolomide); platinumbased agents (cisplatin, carboplatin, and oxaliplatin) [7]; and novel, still under investigation OFF-ONtype alkylating agents such as vinyl-quinazolinone (VQ) [10]. Chemotherapeutics belonging to this class of molecules create either inter or intra-strand cross links or transfer alkyl groups to the guanine residues of DNA, which results in mispair formation in DNA bases and prevents strand separation during DNA synthesis [7,8].…”

Hybridization-specific chemical reactions to create interstrand crosslinking and threaded structures of nucleic acids

“…This vinyl chemistry can also be applied to develop reactive small molecules, and we have reported several compounds. [20][21][22][23][24][25][26] The vinyl derivative-containing oligonucleotides were developed to control gene expression by crosslinking formation. For creating a functional crosslinking structure, we used vinyl chemistry to synthesize crosslinked RNA 27 and 2′-OMe RNA duplexes.…”

Photoactivatable V‐Shaped Bifunctional Quinone Methide Precursors as a New Class of Selective G‐quadruplex Alkylating Agents

“…Up to date, several experiments have highlighted the ability of small synthetic molecules to bind and stabilize G4s in vitro and to interfere with biological processes involving genes containing those structures. [18][19][20][21] Together with reversible G4 ligands, reactive compounds capable of forming covalent bonds with G4 structures upon thermal, [22,23] photochemical, [24,25] target proximity [26,27] and singlet oxygen [28] activation have been developed. The photochemical activation strategies, which include singlet oxygen activation, exploit a new class of promising G4 ligands with the potential to be harnessed for identification and isolation of G4s.…”

“…Together with reversible G4 ligands, reactive compounds capable of forming covalent bonds with G4 structures upon thermal, [22,23] photochemical, [24,25] target proximity [26,27] and singlet oxygen [28] activation have been developed. The photochemical activation strategies, which include singlet oxygen activation, exploit a new class of promising G4 ligands with the potential to be harnessed for identification and isolation of G4s.…”