Synthesis and Biological Evaluation of Indenoisoquinolines That Inhibit Both Tyrosyl-DNA Phosphodiesterase I (Tdp1) and Topoisomerase I (Top1)

Conda‐Sheridan, Martin; Reddy, P. Venkat; Morrell, Andrew; Cobb, Brooklyn T.; Marchand, Christophe; Agama, Keli; Chergui, Adel; Renaud, Amèlie; Stephen, Andrew; Bindu, Lakshman; Pommier, ﻿Yves; Cushman, Mary

doi:10.1021/jm3014458

Cited by 65 publications

(96 citation statements)

References 38 publications

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“…90 °C. 11), 2H-C(12)); 2.53 (tm, 2H, J(10,11)=6.2, 2H-C(10)); 2.71 (tm, 2H, J (13,12)=6.2, 2H-C(13)); 5.09 (s, 2H, 2H-C(14)); 6.84 (d, 1H, J(9,7) = 2.5, H-C(9)); 6.88 (dd, 1H, J(7,6)= 8.8, J (7,9) =2.5, H-C(7)); 7.32 (tt, 1H, J (18,17(19))=7.1, J (18,16(20))=1.5, H-C (18) (20)). 13 C-NMR (CDCl 3 , δ C ): 153.31 (s, C(1)); 161.95 (s, C(2)); 120.54 (s, C(3)); 147.05 (s, C(4)); 113.85 (s, C(5)); 124.00 (d, C(6)); 112.46 (d, C(7)); 160.33 (s, C(8)); 101.60 (d, C(9)); 23.71 (t, C(10)); 21.56 (t, C(11)); 21.26 (t, C(12)); 25.08 (t, C(13)); 70.24 (t, C(14)); 135.93 (s, C(15)); 127.…”

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

“…36 4, H-C(9)); 6.81 (dd, 1H, J(7,6)=8.7, J (7,9)=2.4, H-C(7)); 7.40 (d, 1H, J(6,7)=8.7, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.30 (s, C(1)); 162.12 (s, C(2)); 120.29 (s, C(3)); 147.17 (s, C(4)); 113.54 (s, C(5)); 123.79 (d, C(6)); 112.62 (d, C(7)); 160.69 (s, C(8)); 101.49 (d, C(9)); 23.72 (t, C(10)); 21.60 (t, C(11)); 21.29 (t, C(12)); 25.10 (t, C(13)); 70.93 (t, C(14)); 143.12 (s, C(15)); 121.12 (d, C (16) 16), H-C(20)); 6.85 (d, 1H, J(9,7)=2.5, H-C(9)); 6.89 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.44 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.32 (s, C(1)); 162.00 (s, C(2)); 120.64 (s, C(3)); 147.12 (s, C(4));113.95 (s, C(5)); 124.05 (d, C(6)); 112.50 (d, C(7)); 160.27 (s, C(8)); 101.54 (d, C(9)); 23.72 (t, C(10)); 21.55 (t, C(11)); 21.26 (t, C(12)); 25.11 (t, C(13)); 70.53 (t, C (14) 17)); 6.75 (d, 1H, J(9,7)=2.5, H-C(9)); 6.79 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.41 (d, 1H, J(6,7)=8.8, H-C(6)).…”

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

“…13 C-NMR (CDCl 3 , δ C ): 153.30 (s, C(1)); 162.12 (s, C(2)); 120.29 (s, C(3)); 147.17 (s, C(4)); 113.54 (s, C(5)); 123.79 (d, C(6)); 112.62 (d, C(7)); 160.69 (s, C(8)); 101.49 (d, C(9)); 23.72 (t, C(10)); 21.60 (t, C(11)); 21.29 (t, C(12)); 25.10 (t, C(13)); 70.93 (t, C(14)); 143.12 (s, C(15)); 121.12 (d, C (16) 16), H-C(20)); 6.85 (d, 1H, J(9,7)=2.5, H-C(9)); 6.89 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.44 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.32 (s, C(1)); 162.00 (s, C(2)); 120.64 (s, C(3)); 147.12 (s, C(4));113.95 (s, C(5)); 124.05 (d, C(6)); 112.50 (d, C(7)); 160.27 (s, C(8)); 101.54 (d, C(9)); 23.72 (t, C(10)); 21.55 (t, C(11)); 21.26 (t, C(12)); 25.11 (t, C(13)); 70.53 (t, C (14) 17)); 6.75 (d, 1H, J(9,7)=2.5, H-C(9)); 6.79 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.41 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 153.36 (s, C(1)); 162.12 (s, C(2)); 120.24 (s, C(3)); 147.24 (s, C(4)); 113.49 (c, C(5)); 123.93 (d, C(6)); 112.32 (d, C(7)); 160.64 (s, C(8)); 100.94 (d, C(9)); 23.69 (t, C(10)); 21.27 (t, C(11)); 21.58 (t, C(12)); 25.10 (t, C(13); 66.68 (t, C(14)); 36.11 (t, C(15)); 143.95 (s, C(16)); 118.89 (d, C (17) (7,9)=2.5, H-C(7)); 6.90 (d, 1H, J(9,7)=2.5, H-C(9)); 6.95 (dd, 1H, J (15,17)=2.6, J (15,19)=1.6, H-C(15)); 6.98 (ddd, 1H, J (19,18)=7.6, J (19,15)=1.6, J (19,17)=1.0, H-C(19)); 7.29 (dd, 1H, J (18,17)=8.3, J (18,19)=7.…”

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

“…6, H-C(18)); 7.32 (d, 1H, J(6,7)=9.2, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 155.60 (s, C(1)); 160.32 (s, C(2)); 124.57 (s, C(3)); 156.10 (s, C(4)); 112.55 (s, C(5)); 125.49 (d, C(6)); 112.70 (d, C(7)); 160.89 (s, C(8)); 101.81 (d, C(9)); 30.26 (t, C(10)); 22.45 (t, C(11)); 31.93 (t, C(12)); 70.19 (t, C(13)); 137.45 (s, C(14)); 112.85 (d, C(15)); 159.83 (s, C(16)); 113.62 (d, C (17) 15)), 6.82 (dd, 1H, J(7,6)=8.6, J (7,9)=2.4, H-C(7)); 6.85 (d, 1H, J(9,7)=2.4, H-C(9)); 7.29 (d, 1H, J(6,7)=8.6, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 155.60 (s, C(1)); 160.48 (s, C(2)); 124.28 (s, C(3)); 156.23 (s, C(4)); 112.21 (s, C(5)); 125.28 (d, C(6)); 112.85 (d, C(7)); 161.29 (s, C(8)); 101.67 (d, C(9)); 30.24 (t, C(10)); 22.47 (t, C(11)); 31.93 (t, C(12)); 71.00 (t, C(13)); 143.07 (s, C (14) 6)).…”

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

“…13 C-NMR (CDCl 3 , δ C ): 155.60 (s, C(1)); 160.48 (s, C(2)); 124.28 (s, C(3)); 156.23 (s, C(4)); 112.21 (s, C(5)); 125.28 (d, C(6)); 112.85 (d, C(7)); 161.29 (s, C(8)); 101.67 (d, C(9)); 30.24 (t, C(10)); 22.47 (t, C(11)); 31.93 (t, C(12)); 71.00 (t, C(13)); 143.07 (s, C (14) 6)). 13 C-NMR (CDCl 3 , δ C ): 155.10 (s, C(1)); 161.28 (s, C(2)); 111.74 (d, C(3)); 152.44 (s, C(4)); 113.37 (s, C(5)); 125.21 (d, C(6)); 112.91 (d, C(7)); 161.96 (s, C(8)); 101.75 (d, C(9)); 18.51 (q, C(10)); 71.06 (t, C(11)); 142.96 (s, C(12)); 121.30 (d, C(13)); 31.18 (t, C(14)); 40.70 (d, C(15)); 37.99 (s, C(16)); 43.10 (d, C(17)); 31.39 (t, C(18)); 26.01 (q, C(19)); 20.96 (q, C (20) (18), 3H-C(20)); 5.03 (s, 2H, H-C(11)); 6.12 (q, 1H, J(3,10)=1.2, H-C(3)); 6.63 (s, 2H, H-C(13), H-C(17)); 6.87 (d, 1H, J(9,7)=2.5, H-C(9)); 6.92 (dd, 1H, J(7,6)=8.8, J (7,9)=2.5, H-C(7)); 7.49 (d, 1H, J(6,7)=8.8, H-C(6)). 13 C-NMR (CDCl 3 , δ C ): 155.11 (s, C(1)); 161.06 (s, C(2)); 112.04 (d, C(3)); 152.33 (s, C(4)); 113.76 (s, C(5)); 125.47 (d, C(6)); 112.78 (d, C (7)); 161.50 (s, C(8)); 101.80 (d, C(9)); 18.52 (q, C(10)); 70.64 (t, C(11)); 131.22 (s, C(12)); 104.57 (d, C(13), C(17)); 153.46 (s, C (14), C(16)); 137.96 (s, C(15)); 56.07 (q, C(18), C(20)); 60.72 (q, C (19) …”

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

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New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

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Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

Section: Synthesis Of Compounds 6 24b-e 25a-e and 26a-dmentioning

confidence: 99%

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New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

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Odarchenko

et al. 2016

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Synthesis of Fused Cyclopentenones through Palladium‐Catalyzed Cyclization of 2‐Iodoaryl Allenols

et al. 2014

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The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl‐DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

Keil

Frese-Schaper

Steiner

et al. 2015

Arthritis & Rheumatology

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Objective. The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan.Methods. NZB/NZW mice were treated with lowdose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of antidouble-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay.Results. Compared to treatment with either agent alone, simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/ NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti-dsDNA antibodies. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding.Conclusion. Affecting DNA relaxation by the enzymes topo I and TDP-1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.Systemic lupus erythematosus (SLE) is a chronic autoimmune disease mainly affecting women of childbearing age. It is estimated that in the US up to 275,000 adult women have SLE (1). The disease involves different organs, but immune complex glomerulonephritis most strikingly influences the course of SLE. Between 10% and 30% of patients with lupus nephritis develop end-stage renal disease (ESRD) resulting in the requirement for hemodialysis or kidney transplantation (2). Due to the application of immunosuppressive drugs, the survival of patients with lupus-associated glomerulonephritis increased from a 5-year rate of 44% in the 1950s to a 10-year rate of 88% recently (3). Despite these advances in the treatment of SLE, the life expectancy of patients with lupus and renal damage was recently demonstrated to be 23.7 years shorter than that in the general population (4). Moreover, the incidence of ESRD associated with lupus nephritis did not decrease over recent years (5), indicating that current medication is insufficient to treat lupus nephritis.Treatment with nonselective immunosuppressive drugs continues to be the central strategy for controlling lupus nephritis. Treatment consists of induction therapy with cyclophosphamide and prednisolone or mycophenolate mofetil follow...

show abstract

Synthesis and Biological Evaluation of Indenoisoquinolines That Inhibit Both Tyrosyl-DNA Phosphodiesterase I (Tdp1) and Topoisomerase I (Top1)

Cited by 65 publications

References 38 publications

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

Synthesis of Fused Cyclopentenones through Palladium‐Catalyzed Cyclization of 2‐Iodoaryl Allenols

The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl‐DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

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