Targeting radiosensitizers to DNA by minor groove binding: nitroarenes based on netropsin and distamycin

doi:10.1016/S0960-894X(00)80045-1

Bioorganic & Medicinal Chemistry Letters

Volume 3, Issue 8, August 1993, Pages 1697-1702

https://doi.org/10.1016/S0960-894X(00)80045-1 Get rights and content

Abstract

Four analogues of the antitumour antibiotics, netropsin and distamycin, containing 2-nitroimidazole or 5-nitrofuran moieties were synthesised. All showed high affinity for DNA, including compounds with only one pyrrole/amidine moiety, but the radiosensitizing efficiencies were poor. The results have implications both for minor groove targeting and the design of radiosensitizers.

The compounds bind strongly to DNA, even when n = 1. This finding is of relevance to other chemotherapeutic agents acting on DNA, even though radiosensitization is not enhanced by targeting in this way.

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Molecular dynamics of d(CGCGAATTCGCG)<inf>2</inf> complexed with netropsin and its minor groove methylating analog, Me-lex, using explicit and implicit water models
2009, Journal of Molecular Structure: THEOCHEM
Me-lex, {1-methyl-4-[1-methyl-4-[3-(methoxysulfonyl)-propanamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido}-propane}, a neutral methyl sulfonate analog of netropsin lacking the cationic tails, methylates adenines in the minor groove of DNA at the same A/T rich sequences targeted by netropsin, suggesting that minor groove recognition at A/T sequences can be achieved without the ionic and hydrogen bonding interactions involving the tails of such molecules. Molecular dynamics simulations have been performed on the complexes of the Dickerson-Drew dodecamer, d(CGCGAATTCGCG), with Me-lex and netropsin and their binding interactions have been compared. Simulations have been conducted with an explicit solvent model and the Generalized Born (GB) implicit solvent model. The central bispyrrole triamide unit in both molecules establish similar interactions within the groove. The propyl and methyl sulfonate tails of Me-lex exhibit significant conformational flexibility, and the propyl group causes large variations in the minor groove width in its vicinity. Results obtained using the GB model are very similar to those obtained using the explicit water model. Therefore the computationally efficient GB model can be used to investigate interactions in such systems over longer time scales.
Chemical Radiosensitizers for Use in Radiotherapy
2007, Clinical Oncology
Citation Excerpt :
The topic of DNA targeted radiosensitizing drugs has attracted attention [101]. Examples include nitroimidazole/intercalator conjugates [102,103], nitroacridines (e.g. nitracrine*) and nitroquinoline intercalators [104], minor groove binders [105], and polyamine conjugates [106]. Even pimonidazole was shown to be ‘concentrated’ near DNA relative to misonidazole [107,108].
Radiosensitizers are intended to enhance tumour cell killing while having much less effect on normal tissues. Some drugs target different physiological characteristics of the tumour, particularly hypoxia associated with radioresistance. Oxygen is the definitive hypoxic cell radiosensitizer, the large differential radiosensitivity of oxic vs hypoxic cells being an attractive factor. The combination of nicotinamide to reduce acute hypoxia with normobaric carbogen breathing is showing clinical promise. ‘Electron-affinic’ chemicals that react with DNA free radicals have the potential for universal activity to combat hypoxia-associated radioresistance; a nitroimidazole, nimorazole, is clinically effective at tolerable doses. Hypoxia-specific cytotoxins, such as tirapazamine, are valuable adjuncts to radiotherapy. Nitric oxide is a potent hypoxic cell radiosensitizer; variations in endogenous levels might have prognostic significance, and routes to deliver nitric oxide specifically to tumours are being developed. In principle, many drugs can be delivered selectively to hypoxic tumours using either reductase enzymes or radiation-produced free radicals to activate drug release from electron-affinic prodrugs. A redox-active agent based on a gadolinium chelate is being evaluated clinically. Pyrimidines substituted with bromine or iodine are incorporated into DNA and enhance free radical damage; fluoropyrimidines act by different mechanisms. A wide variety of drugs that influence the nature or repair of DNA damage are being evaluated in conjunction with radiation; it is often difficult to define the mechanisms underlying chemoradiation regimens. Drugs being evaluated include topoisomerase inhibitors (e.g. camptothecin, topotecan), and the hypoxia-activated anthraquinone AQ4N; alkylating agents include temozolomide. Drugs involved in DNA repair pathways being investigated include the potent poly(ADP ribose)polymerase inhibitor, AG14361. Proteins involved in cell signalling, such as the Ras family, are attractive targets linked to radioresistance, as are epidermal growth factor receptors and linked kinases (drugs including vandetanib [ZD6474], cetuximab and gefitinib), and cyclooxygenase-2 (celecoxib). The suppression of radioprotective thiols seems to offer more potential with alkylating agents than with radiotherapy, although it remains a strategy worthy of exploration.
Sequence-specific recognition and modification of double-helical DNA by minor-groove binding conjugates structurally related to netropsin and distamycin
1998, Advances in DNA Sequence-Specific Agents
Netropsin and distamycin have largely contributed to the understanding of the molecular basis of drug-DNA recognition. The understanding of how these two antibiotics recognize and bind to AT sequences in DNA gave perceptions of how to design sequence-specific DNA binding molecules. The knowledge arising from these two antibiotics has inspired the rational design of DNA reading molecules. This chapter shows that the chemical structure of netropsin-like DNA reading elements may be varied in many synthetically convenient fashions, to produce different repertoires of sequence-selective DNA binding molecules with a range of functionalities. Sterically demanding groups can be attached to netropsin and distamycin without abolishing their sequence recognition properties. The fact that certain netropsin analogues can readily recognize a specific sequence in DNA shows DNA targeting with minor-groove binding drugs is no longer a possibility but a practical reality. There is good reason to believe that netropsin and distamycin will continue to inspire the development of new anticancer agents. In the many examples presented in the chapter, netropsin and distamycin are almost always used to deliver cytotoxic drugs to specific sequences in DNA, but they can also be used to deliver DNA to cells.
Synthesis, in vitro aerobic and hypoxic cytotoxicity and radiosensitizing activity of novel metronidazole tethered 5-fluorouracil
2013, DARU, Journal of Pharmaceutical Sciences
Solid phase synthesis of a metronidazole oligonucleotide conjugate
2006, Molecules
Sequence-specific DNA minor groove binders. Design and synthesis of netropsin and distamycin analogues
1998, Bioconjugate Chemistry

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Targeting radiosensitizers to DNA by minor groove binding: nitroarenes based on netropsin and distamycin

Abstract

Biochem. Pharmac.

Int. J. Radiat. Oncol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Radiat. Phys. Chem.

Int. J. Radiat. Oncol. Biol. Phys.

Prog. Biophys. Mol. Biol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Br. J. Radiol.

Pharmacol. Therap.

Radiat. Res.

Cancer Res.

Radiat. Res.