- Email: [email protected]
Synthesis of aza-naphthindolizinedione derivatives
Available online at www.sciencedirect.com
Chinese Chemical Letters 19 (2008) 533–536 www.elsevier.com/locate/cclet
Synthesis of aza-naphthindolizinedione derivatives De Qing Shen, Yu Cheng, Lin Kun An *, Xian Zhang Bu, Zhi Shu Huang, Lian Quan Gu School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China Received 3 January 2008
Abstract A series of aza-naphthindolizinedione derivatives, such as indolizinoquinolinedione derivatives, indolizinophthalazinedione derivatives and indolizinoquinoxalinedione derivatives were designed and synthesized. The synthetic pathway was also proposed. # 2008 Lin Kun An. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Synthesis; Indolizinoquinolinedione; Indolizinophthalazinedione; Indolizinoquinoxalinedione
Camptothecine derivatives, the well-known topoisomerase I (TOP1) inhibitors, are successfully developed as anticancer drug [1,2]. Camptothecine derivatives contain indolizino[1,2-b]quinoline nucleus [3], which is reported to be pharmacologically active moiety [4]. According to Moore theory [5], the molecules contain a planar polycyclic aromatic ring and a conjugated p-quinone attends to be the DNA-intercalating TOP inhibitors [6–8]. It is reported that the naphthindolizinedione derivatives had strong cytotoxic activities [9]. However, there is no report on the cytotoxic activity of aza-naphthindolizinedione derivatives. For this reason, we designed and synthesized the title compounds which combine the indolizine with the aza-1,4-naphthoquinone moiety [7]. A series of indolizinoquinoline-5,12-dione derivatives (shown in Scheme 1) were synthesized using a published method with slight modification [10,11]. 6,7-Dichloroquinoline-5,8-dione (1) was obtained according to Shaikh method by oxidizing of 8-hydroxyquinoline in concentrated HCl solution with sodium chlorate [7]. Unfortunately, the actual yield was only 18%. At the same time, several by-products were obtained from this procedure. Their structures and possible synthetic pathway were shown as Scheme 2. For substrate 11, 12, 14 [12] and 15, the yields were 8%, 6%, 10% and 17%, respectively, which implied the reason for the low yield of target product. The electrophilic substitution would spontaneously take place between 8-hydroxyquinoline and chlorine leading to formation of compound 11. Under assistance of protonation at the nitrogen atom, underwent further addition of methanol followed by oxidation produce compound 12. The reaction mechanism might involve the intermediacy of a radical cation generated by electron transfer from quinoline to halogen [13]. Compound 15, 7-chloro-6-hydroxyquinoline-5,8-dione, was reported to be obtained from the reaction of substrate 1 with NaOH solution [7]. In this preparative procedure, the compound 15 was obtained from the reaction of intermediate 13 with hypochlorous acid.
* Corresponding author. E-mail address: [email protected] (L.K. An). 1001-8417/$ – see front matter # 2008 Lin Kun An. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.03.034
534
D.Q. Shen et al. / Chinese Chemical Letters 19 (2008) 533–536
Scheme 1. Synthesis of indolizinoquinoline-5,12-dione derivatives.
The heterocyclic skeleton was formed based on a single-step reaction between substrate 1, pyridine and an active methylene reagent (AMR). Two regioisomers (N,N-syn and N,N-anti isomers) were obtained in the cyclization, which was different from Yanni’s result [10]. Each isomer was isolated in pure form by silicon gel flash column chromatography and fully characterized by mass spectrometry, elementary analysis and NMR analysis [14]. The indolizinophthalazinedione derivatives (18 and 19) were prepared through cyclization of 6,7-dichlorophthalazine-5,8-dione (16), ethyl acetoacetate and pyridine derivatives (Scheme 3) [14]. The substrate 16 was synthesized using phthalazine as starting material through nitration, hydrogenation and oxidation–chlorination by concentration HNO3 [15,16]. Ethyl-10-fluoro-5,12-dioxo-5,12-dihydroindolizino[3,2-g]quinoxaline-11-carboxylate (20, Scheme 3) was prepared through cyclization of 6,7-dichloroquinoxaline-5,8-dione (17) ethyl acetoacetate and 3-fluoropyridine. The substrate 17 was synthesized using 3-amino-2-nitrophenol as starting material [14], which was hydrogenated and
Scheme 2. Structures and their possible reaction mechanism of compounds 11, 12, 14 and 15.
D.Q. Shen et al. / Chinese Chemical Letters 19 (2008) 533–536
535
Scheme 3. Synthesis of compounds 18–20.
followed by condensation with glyoxal to give the substrate 21 [17]. The substrate 21 was oxidized with Fremy’s salt to give the quinine yellow product 22 in 58% [18], which was chlorinated with thiazyl chloride to give the substrate 17 [19]. Some of the synthetic compounds show significant cytotoxic activities. The detail results of biological activity will be reported in other paper. Acknowledgments The program is sponsored by the NSFC/RGC Joint Research Scheme (No. 20710006), National Natural Science Foundation (No. 20772159) and Guangdong Natural Science Foundation (No. 04300306). References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
W.K. Eng, L. Faucette, R.K. Johnson, et al. Mol. Pharmacol. 34 (1988) 755. J. Nitiss, J.C. Wang, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 7501. M.E. Wall, M.C. Wani, Cancer Res. 55 (1995) 753. T. Hirosawa, Proc. Jpn. Pharmacol. Soc. 12 (1938) 218. M.H. Moore, W.H. Hunter, B.L. d’Estaintot, et al. J. Mol. Biol. 206 (1989) 693. H.J. Park, H.J. Lee, E.J. Lee, et al. Biosci. Biotechnol. Biochem. 67 (2003) 1944. I.A. Shaikh, F. Johnson, A.P. Grollman, J. Med. Chem. 29 (1986) 1329. M.E. Suh, M.J. Kang, S.Y. Park, Bioorg. Med. Chem. 9 (2001) 2987. A. Defant, G. Guella, I. Mancini, Arch. Pharm. Chem. Life Sci. 340 (2007) 147. A.S. Yanni, Collect. Czech. Chem. Commun. 56 (1991) 695. A. Defant, G. Guella, I. Mancini, Eur. J. Org. Chem. 18 (2006) 4201. Y. Cheng, L.K. An, L.Q. Gu, et al. Acta Cryst. E63 (2007) o1365. A.N. Parker, L. Strekowski, Heterocyclic Commun. 4 (1998) 493. The mass and NMR data of compounds 2a and 2b are similar to the Defant’s result (ref. [11]). Compound 18: red solid, yield 21%. C17H10FN3O4, calcd: C, 60.18; H, 2.97; F, 5.60; N, 12.39; O, 18.86; found: C, 60.15; H, 2.99; F, 5.61; N, 12.43. m.p. = 160–162 8C. ESI-MS m/ z: [M+1]+. 1H NMR (300 MHz, CDCl3, d ppm): 9.97 (s, 1H), 9.86 (s, 1H), 9.50 (d, 1H, J = 6.6 Hz), 7.22–7.13 (m, 2H), 4.54 (q, 2H, J = 7.2 Hz),
536
[15] [16] [17] [18] [19]
D.Q. Shen et al. / Chinese Chemical Letters 19 (2008) 533–536 1.47 (t, 3H, J = 7.2 Hz). Compound 19: red solid, yield 13%. C17H10ClN3O4, calcd: C, 57.40; H, 2.83; Cl, 9.97; N, 11.81; O, 17.99; found: C, 57.40; H, 2.84; Cl, 9.94; N, 11.83. m.p. = 220–222. ESI-MS m/z: 355.0, 357.0 [M] . 1H NMR (300 MHz, DMSO-d6, d ppm): 9.92 (s, 1H), 9.80 (s, 1H), 9.57 (d, 1H, J = 6.9 Hz), 7.81 (d, 1H, J = 7.8 Hz), 7.48 (t, 1H, J = 7.2 Hz), 4.50 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz). Compound 20: Red solid, yield 18%. C17H10FN3O4, calcd: C, 60.18; H, 2.97; F, 5.60; N, 12.39; O, 18.86; found: C, 60.18; H, 2.31; F, 5.69; N, 12.36. m.p. = 214–216 8C. ESI-MS m/z: 340.1 [M+1]+, 362.1 [M+Na]+. 1H NMR (300 MHz, CDCl3, d ppm): 9.61 (d, 1H, J = 6.6 Hz), 9.01 (d, 2H, J = 5.1 Hz), 7.19–7.11 (m, 2H), 4.55 (q, 2H, J = 6.9 Hz), 1.48 (t, 3H, J = 7.2 Hz). J.S. Kim, K.J. Shin, D.C. Kim, et al. Bull. Korean Chem. Soc. 23 (2002) 1425. C.K. Ryu, R.E. Park, M.Y. Ma, et al. Bioorg. Med. Chem. Lett. 17 (2007) 2577. H.J. Chung, O.J. Jung, M.J. Chae, et al. Bioorg. Med. Chem. Lett. 15 (2005) 3380. H.M. Chang, K.P. Cheng, T.F. Choang, et al. J. Org. Chem. 55 (1990) 3537. S. Shi, T.J. Katz, B.V. Yang, et al. J. Org. Chem. 60 (1996) 1285.
Chinese Chemical Letters 19 (2008) 533–536 www.elsevier.com/locate/cclet
Synthesis of aza-naphthindolizinedione derivatives De Qing Shen, Yu Cheng, Lin Kun An *, Xian Zhang Bu, Zhi Shu Huang, Lian Quan Gu School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China Received 3 January 2008
Abstract A series of aza-naphthindolizinedione derivatives, such as indolizinoquinolinedione derivatives, indolizinophthalazinedione derivatives and indolizinoquinoxalinedione derivatives were designed and synthesized. The synthetic pathway was also proposed. # 2008 Lin Kun An. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Synthesis; Indolizinoquinolinedione; Indolizinophthalazinedione; Indolizinoquinoxalinedione
Camptothecine derivatives, the well-known topoisomerase I (TOP1) inhibitors, are successfully developed as anticancer drug [1,2]. Camptothecine derivatives contain indolizino[1,2-b]quinoline nucleus [3], which is reported to be pharmacologically active moiety [4]. According to Moore theory [5], the molecules contain a planar polycyclic aromatic ring and a conjugated p-quinone attends to be the DNA-intercalating TOP inhibitors [6–8]. It is reported that the naphthindolizinedione derivatives had strong cytotoxic activities [9]. However, there is no report on the cytotoxic activity of aza-naphthindolizinedione derivatives. For this reason, we designed and synthesized the title compounds which combine the indolizine with the aza-1,4-naphthoquinone moiety [7]. A series of indolizinoquinoline-5,12-dione derivatives (shown in Scheme 1) were synthesized using a published method with slight modification [10,11]. 6,7-Dichloroquinoline-5,8-dione (1) was obtained according to Shaikh method by oxidizing of 8-hydroxyquinoline in concentrated HCl solution with sodium chlorate [7]. Unfortunately, the actual yield was only 18%. At the same time, several by-products were obtained from this procedure. Their structures and possible synthetic pathway were shown as Scheme 2. For substrate 11, 12, 14 [12] and 15, the yields were 8%, 6%, 10% and 17%, respectively, which implied the reason for the low yield of target product. The electrophilic substitution would spontaneously take place between 8-hydroxyquinoline and chlorine leading to formation of compound 11. Under assistance of protonation at the nitrogen atom, underwent further addition of methanol followed by oxidation produce compound 12. The reaction mechanism might involve the intermediacy of a radical cation generated by electron transfer from quinoline to halogen [13]. Compound 15, 7-chloro-6-hydroxyquinoline-5,8-dione, was reported to be obtained from the reaction of substrate 1 with NaOH solution [7]. In this preparative procedure, the compound 15 was obtained from the reaction of intermediate 13 with hypochlorous acid.
* Corresponding author. E-mail address: [email protected] (L.K. An). 1001-8417/$ – see front matter # 2008 Lin Kun An. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.03.034
534
D.Q. Shen et al. / Chinese Chemical Letters 19 (2008) 533–536
Scheme 1. Synthesis of indolizinoquinoline-5,12-dione derivatives.
The heterocyclic skeleton was formed based on a single-step reaction between substrate 1, pyridine and an active methylene reagent (AMR). Two regioisomers (N,N-syn and N,N-anti isomers) were obtained in the cyclization, which was different from Yanni’s result [10]. Each isomer was isolated in pure form by silicon gel flash column chromatography and fully characterized by mass spectrometry, elementary analysis and NMR analysis [14]. The indolizinophthalazinedione derivatives (18 and 19) were prepared through cyclization of 6,7-dichlorophthalazine-5,8-dione (16), ethyl acetoacetate and pyridine derivatives (Scheme 3) [14]. The substrate 16 was synthesized using phthalazine as starting material through nitration, hydrogenation and oxidation–chlorination by concentration HNO3 [15,16]. Ethyl-10-fluoro-5,12-dioxo-5,12-dihydroindolizino[3,2-g]quinoxaline-11-carboxylate (20, Scheme 3) was prepared through cyclization of 6,7-dichloroquinoxaline-5,8-dione (17) ethyl acetoacetate and 3-fluoropyridine. The substrate 17 was synthesized using 3-amino-2-nitrophenol as starting material [14], which was hydrogenated and
Scheme 2. Structures and their possible reaction mechanism of compounds 11, 12, 14 and 15.
D.Q. Shen et al. / Chinese Chemical Letters 19 (2008) 533–536
535
Scheme 3. Synthesis of compounds 18–20.
followed by condensation with glyoxal to give the substrate 21 [17]. The substrate 21 was oxidized with Fremy’s salt to give the quinine yellow product 22 in 58% [18], which was chlorinated with thiazyl chloride to give the substrate 17 [19]. Some of the synthetic compounds show significant cytotoxic activities. The detail results of biological activity will be reported in other paper. Acknowledgments The program is sponsored by the NSFC/RGC Joint Research Scheme (No. 20710006), National Natural Science Foundation (No. 20772159) and Guangdong Natural Science Foundation (No. 04300306). References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
W.K. Eng, L. Faucette, R.K. Johnson, et al. Mol. Pharmacol. 34 (1988) 755. J. Nitiss, J.C. Wang, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 7501. M.E. Wall, M.C. Wani, Cancer Res. 55 (1995) 753. T. Hirosawa, Proc. Jpn. Pharmacol. Soc. 12 (1938) 218. M.H. Moore, W.H. Hunter, B.L. d’Estaintot, et al. J. Mol. Biol. 206 (1989) 693. H.J. Park, H.J. Lee, E.J. Lee, et al. Biosci. Biotechnol. Biochem. 67 (2003) 1944. I.A. Shaikh, F. Johnson, A.P. Grollman, J. Med. Chem. 29 (1986) 1329. M.E. Suh, M.J. Kang, S.Y. Park, Bioorg. Med. Chem. 9 (2001) 2987. A. Defant, G. Guella, I. Mancini, Arch. Pharm. Chem. Life Sci. 340 (2007) 147. A.S. Yanni, Collect. Czech. Chem. Commun. 56 (1991) 695. A. Defant, G. Guella, I. Mancini, Eur. J. Org. Chem. 18 (2006) 4201. Y. Cheng, L.K. An, L.Q. Gu, et al. Acta Cryst. E63 (2007) o1365. A.N. Parker, L. Strekowski, Heterocyclic Commun. 4 (1998) 493. The mass and NMR data of compounds 2a and 2b are similar to the Defant’s result (ref. [11]). Compound 18: red solid, yield 21%. C17H10FN3O4, calcd: C, 60.18; H, 2.97; F, 5.60; N, 12.39; O, 18.86; found: C, 60.15; H, 2.99; F, 5.61; N, 12.43. m.p. = 160–162 8C. ESI-MS m/ z: [M+1]+. 1H NMR (300 MHz, CDCl3, d ppm): 9.97 (s, 1H), 9.86 (s, 1H), 9.50 (d, 1H, J = 6.6 Hz), 7.22–7.13 (m, 2H), 4.54 (q, 2H, J = 7.2 Hz),
536
[15] [16] [17] [18] [19]
D.Q. Shen et al. / Chinese Chemical Letters 19 (2008) 533–536 1.47 (t, 3H, J = 7.2 Hz). Compound 19: red solid, yield 13%. C17H10ClN3O4, calcd: C, 57.40; H, 2.83; Cl, 9.97; N, 11.81; O, 17.99; found: C, 57.40; H, 2.84; Cl, 9.94; N, 11.83. m.p. = 220–222. ESI-MS m/z: 355.0, 357.0 [M] . 1H NMR (300 MHz, DMSO-d6, d ppm): 9.92 (s, 1H), 9.80 (s, 1H), 9.57 (d, 1H, J = 6.9 Hz), 7.81 (d, 1H, J = 7.8 Hz), 7.48 (t, 1H, J = 7.2 Hz), 4.50 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz). Compound 20: Red solid, yield 18%. C17H10FN3O4, calcd: C, 60.18; H, 2.97; F, 5.60; N, 12.39; O, 18.86; found: C, 60.18; H, 2.31; F, 5.69; N, 12.36. m.p. = 214–216 8C. ESI-MS m/z: 340.1 [M+1]+, 362.1 [M+Na]+. 1H NMR (300 MHz, CDCl3, d ppm): 9.61 (d, 1H, J = 6.6 Hz), 9.01 (d, 2H, J = 5.1 Hz), 7.19–7.11 (m, 2H), 4.55 (q, 2H, J = 6.9 Hz), 1.48 (t, 3H, J = 7.2 Hz). J.S. Kim, K.J. Shin, D.C. Kim, et al. Bull. Korean Chem. Soc. 23 (2002) 1425. C.K. Ryu, R.E. Park, M.Y. Ma, et al. Bioorg. Med. Chem. Lett. 17 (2007) 2577. H.J. Chung, O.J. Jung, M.J. Chae, et al. Bioorg. Med. Chem. Lett. 15 (2005) 3380. H.M. Chang, K.P. Cheng, T.F. Choang, et al. J. Org. Chem. 55 (1990) 3537. S. Shi, T.J. Katz, B.V. Yang, et al. J. Org. Chem. 60 (1996) 1285.