“…The synthesis of six of the seven molecular compounds was published previously: HNAF-1 [ 58 ], PSTHQ-2 [ 59 ], PSTHQ-13 [ 60 ], NAF-15 [ 61 ], NAF-17 [ 62 ], and NAF-18 [ 62 ]. General experimental information is described in Tejeria et al [ 60 ], and the synthesis of NAF-POEt is described in Appendix A and Figure A1 .…”
Section: Methodsmentioning
confidence: 99%
“…For the preparation of the derivatives HNAF-1 (X = N, R1 = H), PSTHQ-2 (X = CH, R1 = P(S)Ph 2 ), and PSTHQ-13 (X = CH, R1 = P(S)Ph 2 ), to the aldimine 3 solution an equimolecular amount of styrene 4 was added and the mixture was stirred in refluxing chloroform in the presence of the Lewis acid (BF 3 ·Et 2 O) affording the corresponding derivatives HNAF-1 [ 58 ] , PSTHQ-2 [ 59 ] , and PSTHQ-13 [ 60 ] regio- and stereoselectively as previously reported. For preparation of the derivatives NAF-15 [ 61 ] , NAF-17 [ 62 ] , NAF-18 [ 62 ] , and NAF-POEt , aldimines 3 were prepared from amine 1a (X = N, R 1 = H) and reacted in situ with an equimolecular amount of the corresponding acetylenic derivative 5 in the presence of BF 3 ·Et 2 O in chloroform at reflux, and the corresponding heterocyclic derivatives were obtained regioselectively. Figure A1 Povarov reaction for the syntheses of HNAF-1, PSTHQ-2, PSTHQ-13, NAF-15, NAF-17, NAF-18, and NAF-POEt.…”
Section: Appendix A1 Chemical Synthesis Of Heterocyclic Compounds and Experimental Data Of Naf-poetmentioning
DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.
“…The synthesis of six of the seven molecular compounds was published previously: HNAF-1 [ 58 ], PSTHQ-2 [ 59 ], PSTHQ-13 [ 60 ], NAF-15 [ 61 ], NAF-17 [ 62 ], and NAF-18 [ 62 ]. General experimental information is described in Tejeria et al [ 60 ], and the synthesis of NAF-POEt is described in Appendix A and Figure A1 .…”
Section: Methodsmentioning
confidence: 99%
“…For the preparation of the derivatives HNAF-1 (X = N, R1 = H), PSTHQ-2 (X = CH, R1 = P(S)Ph 2 ), and PSTHQ-13 (X = CH, R1 = P(S)Ph 2 ), to the aldimine 3 solution an equimolecular amount of styrene 4 was added and the mixture was stirred in refluxing chloroform in the presence of the Lewis acid (BF 3 ·Et 2 O) affording the corresponding derivatives HNAF-1 [ 58 ] , PSTHQ-2 [ 59 ] , and PSTHQ-13 [ 60 ] regio- and stereoselectively as previously reported. For preparation of the derivatives NAF-15 [ 61 ] , NAF-17 [ 62 ] , NAF-18 [ 62 ] , and NAF-POEt , aldimines 3 were prepared from amine 1a (X = N, R 1 = H) and reacted in situ with an equimolecular amount of the corresponding acetylenic derivative 5 in the presence of BF 3 ·Et 2 O in chloroform at reflux, and the corresponding heterocyclic derivatives were obtained regioselectively. Figure A1 Povarov reaction for the syntheses of HNAF-1, PSTHQ-2, PSTHQ-13, NAF-15, NAF-17, NAF-18, and NAF-POEt.…”
Section: Appendix A1 Chemical Synthesis Of Heterocyclic Compounds and Experimental Data Of Naf-poetmentioning
DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.
“…The cycloaddition proceeds through endo transition states to afford tetrahydro-1,5-naphthyridines 37a – c with the control of two stereocenters. Subsequent aromatization afforded the corresponding 4-phenyl-1,5-naphthyridines [ 45 , 46 ]. 1,5-Naphthyridine derivatives 37d – j were prepared by a modification of a Diels-Alder reaction between aldimines 35 , derived from 3-aminopyridine and vinyl acetamide 36 (R 3 = NHCOMe) to give the corresponding racemic mixture of the cis isomers ( Scheme 12 ) [ 47 ].…”
Section: Synthesis Of 15-naphthyridinesmentioning
confidence: 99%
“…In 2018, a wide range of substituted 1,5-naphthyridines showed antileishmanial activity on promastigotes and amastigote-infected splenocytes of L. infantum [ 46 ]. These 1,5-naphthyridines displayed higher antiparasitic activity on intracellular amastigotes than on free-living promastigotes.…”
Section: Applications Of 15-naphthyridinesmentioning
This review covers the synthesis and reactivity of 1,5-naphthyridine derivatives published in the last 18 years. These heterocycles present a significant importance in the field of medicinal chemistry because many of them exhibit a great variety of biological activities. First, the published strategies related to the synthesis of 1,5-naphthyridines are presented followed by the reactivity of these compounds with electrophilic or nucleophilic reagents, in oxidations, reductions, cross-coupling reactions, modification of side chains or formation of metal complexes. Finally, some properties and applications of these heterocycles studied during this period are examined.
“…Accordingly, several families of compounds with nitrogen-containing heterocyclic scaffolds have been successfully presented as drug candidates for TOP1B inhibitors [ 8 ]. In this sense, our group has developed the synthesis of nitrogen-containing heterocycles, such as 1,5-naphthyridine [ 9 ] derivatives, and studied their biological activity, showing good results as TOP1B inhibitors with antiproliferative [ 10 , 11 ] and antileishmanial [ 12 , 13 ] activity. In this regard, quinoline is considered a privileged scaffold in cancer drug discovery and quinoline involving central cores are of particular relevance in drugs/candidates with TOP1B inhibition-based mode of action [ 14 , 15 , 16 , 17 ].…”
This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation. In the current report, a new series of dialkyl (2-arylquinolin-8-yl)phosphonates have been synthesized and their antiproliferative effect evaluated on different human cancer and embryonic cells, as well as on Leishmania infantum parasites, a eukaryotic protist responsible for visceral leishmaniasis. Thereby, the antitumor effect was assessed in human lung adenocarcinoma cells (A549), human ovarian carcinoma cells (SKOV3), and human embryonic kidney cells (HEK293) versus the non-cancerous lung fibroblasts cell line (MRC5). On the other hand, the antileishmanial activity was tested against both stages of L. infantum cell cycle, namely free-living promastigotes and intramacrophage amastigotes, using a primary culture of Balb/c splenocytes to calculate the selectivity index. Besides the antiproliferative and antileishmanial capacities, their behavior as topoisomerase 1B inhibitors has been evaluated as a possible mechanism of action.
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