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Hypoxia-selective agents derived from 2-quinoxalinecarbonitrile 1,4-di-N-oxides. 2
A Monge1, F J Martínez-Crespo, A López de Ceráin
1Department of Medicinal Chemistry, CIFA, Universidad de Navarra, Pamplona, Spain.
Abstract:
Hypoxic cells are an important target for antitumor therapy because tumors are typically characterized by such cells. Virtually all tumors which are present as solid masses contain hypoxic cells, while normal cells generally have an adequate supply of oxygen. Accordingly, antitumor agents can be made selective for tumors by virtue of high activity under hypoxic conditions. The initial purpose of this work was to determine the influence of different groups in position 3. Thus, the synthesis of some 3-NH-substituted derivatives (2a, 3a, 4a) starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide (1a) is described. Reductive deamination of compounds 1a-k provides the 2-quinoxalinecarbonitriles 5a-k, which are more potent, while selectivity is maintained or increased in some derivatives. The compound 7-(4-nitrophenyl)-2-quinoxalinecarbonitrile 1,4-di-N-oxide (5k) is 150-fold more potent than tirapazamine (3-amino-1,2,4- benzotriazine 1,4-di-N-oxide), which has been used as a standard. Three derivatives (5g,i,k) show a hypoxic cytotoxicity ratio (HCR) > or = 200, better than that of tirapazamine (HCR = 75) in V79 cells. Replacement of the 3-amino group by chlorine affords the potent but nonselective 3-chloro derivatives 6a-k showing similar toxicities under both aerobic and hypoxic conditions. These compounds were used as intermediates for the synthesis of a new series of water-soluble compounds derived from 3-[[(N,N- dialkylamino)alkyl[amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxides 10a-i and 11a-i. The 7-chloro and the 7-trifluoromethyl derivatives 10b,f have demonstrated high potency (0.4 and 0.3 microM) and excellent selectivity (HCR = 250 and 340). Several 7-chloro analogues, 12b, 13b.1,b.2, and 14b, and the dimer 16b have been prepared and evaluated in order to determine the optimum lateral chain in position 3, which appears to be the [(N,N-dimethylamino)propyl]amino moiety.
Insights
Researchers developed novel hypoxic cell-targeting antitumor agents. These new compounds show superior potency and selectivity compared to existing standards, offering a promising avenue for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Tumors often contain hypoxic cells, making them a key target for selective antitumor therapies.
- Antitumor agents can exploit the oxygen-deprived environment of tumors for targeted efficacy.
- Quinoxaline derivatives are explored for their potential as hypoxia-activated prodrugs.
Purpose of the Study:
- To synthesize and evaluate novel 3-NH-substituted quinoxaline-1,4-di-N-oxides as potential antitumor agents.
- To investigate the structure-activity relationships of these derivatives, focusing on substituents at position 3 and 7.
- To develop water-soluble analogues with improved potency and tumor selectivity.
Main Methods:
- Synthesis of 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide derivatives and their reductive deamination.
- Preparation of 3-chloroquinoxaline derivatives as intermediates.
- Synthesis of novel water-soluble quinoxaline-1,4-di-N-oxides with varying side chains at position 3.
- Evaluation of hypoxic cytotoxicity ratio (HCR) in V79 cells and determination of IC50 values.
Main Results:
- Several synthesized quinoxaline derivatives demonstrated significantly higher potency and selectivity than tirapazamine.
- Compound 5k exhibited 150-fold greater potency than tirapazamine.
- Three derivatives (5g,i,k) achieved HCR values of 200 or greater, outperforming tirapazamine's HCR of 75.
- Water-soluble derivatives, particularly 7-chloro and 7-trifluoromethyl analogues (10b,f), showed high potency (0.3-0.4 microM) and excellent selectivity (HCR 250-340).
- The [(N,N-dimethylamino)propyl]amino moiety at position 3 was identified as optimal for lateral chain activity.
Conclusions:
- Novel quinoxaline-1,4-di-N-oxide derivatives represent a promising class of hypoxia-targeted antitumor agents.
- The introduction of specific substituents at positions 3 and 7 can enhance both potency and tumor selectivity.
- Water-soluble analogues with optimized side chains offer a viable strategy for developing effective cancer therapeutics.