- Email: [email protected]
Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives
Bioorganic & Medicinal Chemistry Letters 22 (2012) 4762–4764
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives Kohji Matsumoto a, Tominari Choshi a,⇑, Mai Hourai a, Yoshito Zamami b, Kenji Sasaki b, Takumi Abe c, Minoru Ishikura c, Noriyuki Hatae d, Tatsunori Iwamura d, Shigeo Tohyama a, Junko Nobuhiro a, Satoshi Hibino a,⇑ a
Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan c Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan d Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2, Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan b
a r t i c l e
i n f o
Article history: Received 24 March 2012 Revised 9 May 2012 Accepted 16 May 2012 Available online 4 June 2012
a b s t r a c t We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4 10 6–1.2 10 7 M. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Calothrixin A Calothrixin B N-Alkyl-calothrixins Indolo[3,2-j]phenanthridine Antimalarial activity
H
Malaria remains one of the most serious infectious diseases in the world. The disease occurs in tropical and subtropical areas, including Africa, Asia, and South America. Plasmodium falciparum and Plasmodium vavax are the two most prevalent species responsible for causing malaria in humans. Quinolines are an important class of antimalarial agents (Fig. 1). Chloroquine (QC) is widely used for the prevention and initial treatment of malaria. The spread of malaria strains resistant to QC and many other antimalarial drugs, however, limits their use. Therefore, the development of new chemotherapeutic agents that are effective against QC-resistant malaria is in high demand. Calothrixin A and B, having a pentacyclic indolo[3,2-j]phenanthridine framework, were isolated from the cyanobacteria Calothrix in 1999.1 These compounds inhibit in vitro growth of the QC-resistant strain of the human parasite Plasmodium falciparum in a dose-dependent manner, and also have lethal effects on the human HeLa cancer cell line.1–6 The synthesis of calothrixins has attracted the interest of several research groups due to their biologic activities and rare pentacyclic framework. Nine synthetic routes to calothrixins have been reported by seven research ⇑ Corresponding authors. E-mail address: [email protected] (T. Choshi). 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.05.064
Me
Et N
HN
H Et
N
HO
MeO Cl
N
N
chloroquine
quinine
O
O O N
N H O 1a: calothrixin A
N N H O 2a: calothrixin B
Figure 1. Chemical structures of chloroquine, quinine, and calothrixins (1a, 2a).
groups: Kelly et al.,7 Chai et al.,8–10 Guingant et al.,11,12 Bennasar et al.,13 Moody et al.,14 Ishikura et al.,15 and us.16–19 In addition, Bernardo and co-workers reported a structure–activity study of calothrixins and their quinone analogues against tumor activity.4
4763
K. Matsumoto et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4762–4764
RO CHO
CHO Br
d)
a)
+
B(OH)2
N H
N N R1 R2 5: R1=H, R2=Boc 6: R1=R2=H 7: R1=R2=MOM
N Boc
3
4
b) c)
MOMO
Me
MOMO f)
e)
N N MOM MOM 8: R=H 9: R=MOM
O
CHO
CHO
h)
g)
N N MOM
N N MOM MOM
N N MOM MOM 10
11
12
O
O N
N
i) N H
N MOM O 13
O 2a
Scheme 1. Reagents and conditions: (a) 2 M Na2CO3, PdCl2(dppf), 80 °C (96%); (b) TFA, 0 °C?rt (99%); (c) MOMCl, NaH, DMF, 0 °C?rt (98%); (d) ethynylmagnesium bromide, THF, 0 °C?rt (98%); (e) MOMCl, iPr2NEt, CH2Cl2, 45 °C (93%); (f) tBuOK, tBuOH–THF, 90 °C (93%); (g) DDQ, DMF, rt (80%); (h) CAN, MeOH–H2O, 0 °C (40%); (i) conc. HCl, THF, 55 °C (86%).
We previously reported two total synthetic routes of calothrixins, in which we used an allene-mediated electrocyclic reaction of the 6p-electron system as a key step in this biomimetic synthetic route.17–19 Here we report the synthesis of N-alkyl-calothrixins and evaluation of their compounds against QC-sensitive malaria aimed at the development of new drug candidates or lead compounds. First, we synthesized calothrixin B using the previously reported biomimetic route shown in Scheme 1.17 A Suzuki coupling reaction of 2-bromoindole-3-carbaldehyde (3) with indole-2-boronic acid 4, followed by cleavage of the Boc group with TFA gave bisindole 6. Treatment of bisindole 6 with chloromethyl methyl ether (MOMCl) and NaH gave the product 7, which was subjected to Grignard reaction with ethynylmagnesium bromide to afford the propargyl alcohol 8. Protection of the hydroxyl group of propargyl alcohol 8 with MOMCl in the presence of iPr2NEt yielded MOM ether 9. MOM ether 9 was subjected to an allene-mediated electrocyclic reaction in the presence of tBuOK in tBuOH–THF at 90 °C to give the indolocarbazole 10. Subsequently, oxidation of indolocarbazole 10 with DDQ gave the 6-formylindolocarbazole 11, which was treated with cerium ammonium nitrate (CAN) to give the NMOM-calothrixin B (13). This result indicated that quinone-imine 12 was formed. Immediate hydrolysis of an imino group in 12, followed by an intramolecular condensation, then occurred to form the indolo[3,2-j]phenanthridine framework. Finally, treatment of N-MOM-calothrixin B (13) with conc. HCl in THF yielded calothrixin B (2a).
O
O N N H
O 2a
We then derived 2a to N-alkyl-calothrixins by alkylation (Scheme 2). Treatment of calothrixin B (2a) with alkyl halide (R = Me, Et, iPr, CH2CH2OH) and NaH afforded the N-alkyl-calothrixin B derivatives 2b–e. Subsequently, oxidation of N-alkyl-calothrixin B derivatives 2b–e with m-chloroperbenzoic acid (mCPBA) gave the calothrixin A derivatives 1b–e. The antimalarial potencies of the calothrixins A (1a), B (2a) and their N-alkylated compounds were evaluated in vitro against the P. falciparum FCR-3 strain (QC-sensitive).20 Chloroquine was used as a positive control. The biologic results are summarized in Table 1. Calothrixin derivatives exhibited antimalarial activity (IC50) against P. falciparum within a concentration range of 6.4 10 6 M to 1.2 10 7 M (runs 1–10). Comparison of the IC50 values revealed that calothrixin B (2a) (run 6) had the highest activity. The IC50 value obtained for calothrixin B (IC50 = 1.2 10 7 M) was in agreement with that of Rickards et al.,1 whereas the IC50 value of calothrixin A (IC50 = 1.85 10 7 M) differed from their result. The antimalarial activity of calothrixin A was as potent as that of calothrixin B in our assay (runs 1, 6). Introduction of an alkyl group in the indole nitrogen atom of the calothrixins decreased the antimalarial activity (runs 2–5, 7–10). In the N-alkylated compounds, 2-hydroxyethyl substitution was more effective for increasing activity than the other substitutions (runs 5, 10). In addition, the IC50 value of N-alkyl-calothrixin A derivatives was greater than that of calothrixin B derivatives. In the case of N-alkylated calothrixin A derivatives (runs 2–5), grater C log P compounds showed more potent inhibitory activity with the exception of run 5
a) or b)
O N
N R
O
2b: R=Me (77%) 2c: R=Et (81%) 2d: R=iPr (62%) 2e: R=CH2CH2OH (96%)
O
c)
N N R
O
1b: R=Me (96%) 1c: R=Et (80%) 1d: R=iPr (58%) 1e: R=CH2CH2OH (61%)
Scheme 2. Reagents and conditions: (a) RI, NaH, THF, rt; (b) RI, NaH, DMF–THF, 60 °C; (c) mCPBA, CH2Cl2, reflux.
4764
K. Matsumoto et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4762–4764
Table 1 In vitro antimalarial activity of calothrixins A (1a–e) and calothrixins B (2a–e) Run
Compd. No.
1 1a 2 1b 3 1c 4 1d 5 1e 6 2a 7 2b 8 2c 9 2d 10 2e Chloroquine
R H Me Et iPr CH2CH2OH H Me Et iPr CH2CH2OH
IC50 against FCR-3 strain (M) 1.85 10 3.8 10 7 3.8 10 7 3.2 10 7 2.5 10 7 1.2 10 7 4.9 10 7 2.2 10 6 6.4 10 6 3.3 10 7 1.8 10 8
7
C log P 2.48 2.85 3.38 3.69 2.02 4.16 4.25 4.78 5.09 3.42
where the alkyl group is CH2CH2OH. On the other hand, as the hydrophobicity in runs 7–10 rose, the inhibitory activity of calothrixin B derivatives became low with similar exception of run 10. These exceptions of compounds 1e and 2e seem to be caused by the other factors like a penetration ability through the blood cell or malarial parasite cell, binding ability to the active site, and so on. In summary, we synthesized calothrixin B using our previously developed biomimetic method and derived two types of N-alkylcalothrixins. The calothrixin derivatives, including natural-occurring compounds, were evaluated for antimalarial activity in vitro. All test compounds exhibited antimalarial activity. Introduction of alkyl group to the indole nitrogen atom, however, decreased the antimalarial activity than that of calothrixins A and B. Thus, the findings of the present study suggest that the pentacyclic indolo[3,2-j]phenanthridine structure of calothrixins is advantageous for antimalarial medicinal chemistry. Acknowledgement This work was partly supported by a Grant-in Aid for Scientific Research of the Japan Society for the promotion of Science (JSPS).
Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012. 05.064. References and notes 1. Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55, 13513. 2. Doan, N. T.; Rickards, R. W.; Rothchild, J. M.; Smith, G. D. J. Appl. Phycol. 2000, 12, 409. 3. Doan, N. T.; Stewart, P. R.; Smith, G. D. FEMS Microbiol. Lett. 2001, 196, 135. 4. Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D.; Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958. 5. Bernardo, P. H.; Chai, C. L. L.; Le Guen, M.; Smith, G. D.; Waring, P. Bioorg. Med. Chem. Lett. 2007, 17, 82. 6. Chen, X. X.; Smith, G. D.; Waring, P. J. Appl. Phycol. 2003, 15, 269. 7. Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000, 3, 3735. 8. Bernardo, P. H.; Chai, C. L. L.; Elix, J. A. Tetrahedron Lett. 2002, 43, 2939. 9. Bernardo, P. H.; Chai, C. L. L. J. Org. Chem. 2003, 68, 8906. 10. Bernardo, P. H.; Fitriyanto, W.; Chai, C. L. L. Synlett 2007, 1935. 11. Sissouma, D.; Collet, S. C.; Guingant, A. Y. Synlett 2004, 2612. 12. Sissouma, D.; Maingot, L.; Collet, S.; Guingant, A. J. Org. Chem. 2006, 71, 8384. 13. Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561. 14. Sperry, J.; McErlean, C. S. P.; Slawin, A. M. Z.; Moody, C. J. Tetrahedron Lett. 2007, 48, 231. 15. Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13, 3356. 16. Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263. 17. Yamabuki, A.; Fujinawa, H.; Choshi, T.; Tohyama, S.; Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2006, 47, 5859. 18. Choshi, T.; Hibino, S. Heterocycles 2009, 77, 85. 19. Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Hieda, Y.; Nobuhiro, J.; Hibino, S. Heterocycles 2010, 82, 397. 20. Fujimoto, K.; Morisaki, D.; Yoshida, M.; Namba, T.; Hye-Sook, K.; Wataya, Y.; Kourai, H.; Kakuta, H.; Sasaki, K. Bioorg. Med. Chem. Lett. 2006, 16, 2758.
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives Kohji Matsumoto a, Tominari Choshi a,⇑, Mai Hourai a, Yoshito Zamami b, Kenji Sasaki b, Takumi Abe c, Minoru Ishikura c, Noriyuki Hatae d, Tatsunori Iwamura d, Shigeo Tohyama a, Junko Nobuhiro a, Satoshi Hibino a,⇑ a
Graduate School of Pharmacy & Pharmaceutical Sciences, and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan c Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan d Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2, Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan b
a r t i c l e
i n f o
Article history: Received 24 March 2012 Revised 9 May 2012 Accepted 16 May 2012 Available online 4 June 2012
a b s t r a c t We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4 10 6–1.2 10 7 M. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Calothrixin A Calothrixin B N-Alkyl-calothrixins Indolo[3,2-j]phenanthridine Antimalarial activity
H
Malaria remains one of the most serious infectious diseases in the world. The disease occurs in tropical and subtropical areas, including Africa, Asia, and South America. Plasmodium falciparum and Plasmodium vavax are the two most prevalent species responsible for causing malaria in humans. Quinolines are an important class of antimalarial agents (Fig. 1). Chloroquine (QC) is widely used for the prevention and initial treatment of malaria. The spread of malaria strains resistant to QC and many other antimalarial drugs, however, limits their use. Therefore, the development of new chemotherapeutic agents that are effective against QC-resistant malaria is in high demand. Calothrixin A and B, having a pentacyclic indolo[3,2-j]phenanthridine framework, were isolated from the cyanobacteria Calothrix in 1999.1 These compounds inhibit in vitro growth of the QC-resistant strain of the human parasite Plasmodium falciparum in a dose-dependent manner, and also have lethal effects on the human HeLa cancer cell line.1–6 The synthesis of calothrixins has attracted the interest of several research groups due to their biologic activities and rare pentacyclic framework. Nine synthetic routes to calothrixins have been reported by seven research ⇑ Corresponding authors. E-mail address: [email protected] (T. Choshi). 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.05.064
Me
Et N
HN
H Et
N
HO
MeO Cl
N
N
chloroquine
quinine
O
O O N
N H O 1a: calothrixin A
N N H O 2a: calothrixin B
Figure 1. Chemical structures of chloroquine, quinine, and calothrixins (1a, 2a).
groups: Kelly et al.,7 Chai et al.,8–10 Guingant et al.,11,12 Bennasar et al.,13 Moody et al.,14 Ishikura et al.,15 and us.16–19 In addition, Bernardo and co-workers reported a structure–activity study of calothrixins and their quinone analogues against tumor activity.4
4763
K. Matsumoto et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4762–4764
RO CHO
CHO Br
d)
a)
+
B(OH)2
N H
N N R1 R2 5: R1=H, R2=Boc 6: R1=R2=H 7: R1=R2=MOM
N Boc
3
4
b) c)
MOMO
Me
MOMO f)
e)
N N MOM MOM 8: R=H 9: R=MOM
O
CHO
CHO
h)
g)
N N MOM
N N MOM MOM
N N MOM MOM 10
11
12
O
O N
N
i) N H
N MOM O 13
O 2a
Scheme 1. Reagents and conditions: (a) 2 M Na2CO3, PdCl2(dppf), 80 °C (96%); (b) TFA, 0 °C?rt (99%); (c) MOMCl, NaH, DMF, 0 °C?rt (98%); (d) ethynylmagnesium bromide, THF, 0 °C?rt (98%); (e) MOMCl, iPr2NEt, CH2Cl2, 45 °C (93%); (f) tBuOK, tBuOH–THF, 90 °C (93%); (g) DDQ, DMF, rt (80%); (h) CAN, MeOH–H2O, 0 °C (40%); (i) conc. HCl, THF, 55 °C (86%).
We previously reported two total synthetic routes of calothrixins, in which we used an allene-mediated electrocyclic reaction of the 6p-electron system as a key step in this biomimetic synthetic route.17–19 Here we report the synthesis of N-alkyl-calothrixins and evaluation of their compounds against QC-sensitive malaria aimed at the development of new drug candidates or lead compounds. First, we synthesized calothrixin B using the previously reported biomimetic route shown in Scheme 1.17 A Suzuki coupling reaction of 2-bromoindole-3-carbaldehyde (3) with indole-2-boronic acid 4, followed by cleavage of the Boc group with TFA gave bisindole 6. Treatment of bisindole 6 with chloromethyl methyl ether (MOMCl) and NaH gave the product 7, which was subjected to Grignard reaction with ethynylmagnesium bromide to afford the propargyl alcohol 8. Protection of the hydroxyl group of propargyl alcohol 8 with MOMCl in the presence of iPr2NEt yielded MOM ether 9. MOM ether 9 was subjected to an allene-mediated electrocyclic reaction in the presence of tBuOK in tBuOH–THF at 90 °C to give the indolocarbazole 10. Subsequently, oxidation of indolocarbazole 10 with DDQ gave the 6-formylindolocarbazole 11, which was treated with cerium ammonium nitrate (CAN) to give the NMOM-calothrixin B (13). This result indicated that quinone-imine 12 was formed. Immediate hydrolysis of an imino group in 12, followed by an intramolecular condensation, then occurred to form the indolo[3,2-j]phenanthridine framework. Finally, treatment of N-MOM-calothrixin B (13) with conc. HCl in THF yielded calothrixin B (2a).
O
O N N H
O 2a
We then derived 2a to N-alkyl-calothrixins by alkylation (Scheme 2). Treatment of calothrixin B (2a) with alkyl halide (R = Me, Et, iPr, CH2CH2OH) and NaH afforded the N-alkyl-calothrixin B derivatives 2b–e. Subsequently, oxidation of N-alkyl-calothrixin B derivatives 2b–e with m-chloroperbenzoic acid (mCPBA) gave the calothrixin A derivatives 1b–e. The antimalarial potencies of the calothrixins A (1a), B (2a) and their N-alkylated compounds were evaluated in vitro against the P. falciparum FCR-3 strain (QC-sensitive).20 Chloroquine was used as a positive control. The biologic results are summarized in Table 1. Calothrixin derivatives exhibited antimalarial activity (IC50) against P. falciparum within a concentration range of 6.4 10 6 M to 1.2 10 7 M (runs 1–10). Comparison of the IC50 values revealed that calothrixin B (2a) (run 6) had the highest activity. The IC50 value obtained for calothrixin B (IC50 = 1.2 10 7 M) was in agreement with that of Rickards et al.,1 whereas the IC50 value of calothrixin A (IC50 = 1.85 10 7 M) differed from their result. The antimalarial activity of calothrixin A was as potent as that of calothrixin B in our assay (runs 1, 6). Introduction of an alkyl group in the indole nitrogen atom of the calothrixins decreased the antimalarial activity (runs 2–5, 7–10). In the N-alkylated compounds, 2-hydroxyethyl substitution was more effective for increasing activity than the other substitutions (runs 5, 10). In addition, the IC50 value of N-alkyl-calothrixin A derivatives was greater than that of calothrixin B derivatives. In the case of N-alkylated calothrixin A derivatives (runs 2–5), grater C log P compounds showed more potent inhibitory activity with the exception of run 5
a) or b)
O N
N R
O
2b: R=Me (77%) 2c: R=Et (81%) 2d: R=iPr (62%) 2e: R=CH2CH2OH (96%)
O
c)
N N R
O
1b: R=Me (96%) 1c: R=Et (80%) 1d: R=iPr (58%) 1e: R=CH2CH2OH (61%)
Scheme 2. Reagents and conditions: (a) RI, NaH, THF, rt; (b) RI, NaH, DMF–THF, 60 °C; (c) mCPBA, CH2Cl2, reflux.
4764
K. Matsumoto et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4762–4764
Table 1 In vitro antimalarial activity of calothrixins A (1a–e) and calothrixins B (2a–e) Run
Compd. No.
1 1a 2 1b 3 1c 4 1d 5 1e 6 2a 7 2b 8 2c 9 2d 10 2e Chloroquine
R H Me Et iPr CH2CH2OH H Me Et iPr CH2CH2OH
IC50 against FCR-3 strain (M) 1.85 10 3.8 10 7 3.8 10 7 3.2 10 7 2.5 10 7 1.2 10 7 4.9 10 7 2.2 10 6 6.4 10 6 3.3 10 7 1.8 10 8
7
C log P 2.48 2.85 3.38 3.69 2.02 4.16 4.25 4.78 5.09 3.42
where the alkyl group is CH2CH2OH. On the other hand, as the hydrophobicity in runs 7–10 rose, the inhibitory activity of calothrixin B derivatives became low with similar exception of run 10. These exceptions of compounds 1e and 2e seem to be caused by the other factors like a penetration ability through the blood cell or malarial parasite cell, binding ability to the active site, and so on. In summary, we synthesized calothrixin B using our previously developed biomimetic method and derived two types of N-alkylcalothrixins. The calothrixin derivatives, including natural-occurring compounds, were evaluated for antimalarial activity in vitro. All test compounds exhibited antimalarial activity. Introduction of alkyl group to the indole nitrogen atom, however, decreased the antimalarial activity than that of calothrixins A and B. Thus, the findings of the present study suggest that the pentacyclic indolo[3,2-j]phenanthridine structure of calothrixins is advantageous for antimalarial medicinal chemistry. Acknowledgement This work was partly supported by a Grant-in Aid for Scientific Research of the Japan Society for the promotion of Science (JSPS).
Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012. 05.064. References and notes 1. Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55, 13513. 2. Doan, N. T.; Rickards, R. W.; Rothchild, J. M.; Smith, G. D. J. Appl. Phycol. 2000, 12, 409. 3. Doan, N. T.; Stewart, P. R.; Smith, G. D. FEMS Microbiol. Lett. 2001, 196, 135. 4. Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D.; Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958. 5. Bernardo, P. H.; Chai, C. L. L.; Le Guen, M.; Smith, G. D.; Waring, P. Bioorg. Med. Chem. Lett. 2007, 17, 82. 6. Chen, X. X.; Smith, G. D.; Waring, P. J. Appl. Phycol. 2003, 15, 269. 7. Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000, 3, 3735. 8. Bernardo, P. H.; Chai, C. L. L.; Elix, J. A. Tetrahedron Lett. 2002, 43, 2939. 9. Bernardo, P. H.; Chai, C. L. L. J. Org. Chem. 2003, 68, 8906. 10. Bernardo, P. H.; Fitriyanto, W.; Chai, C. L. L. Synlett 2007, 1935. 11. Sissouma, D.; Collet, S. C.; Guingant, A. Y. Synlett 2004, 2612. 12. Sissouma, D.; Maingot, L.; Collet, S.; Guingant, A. J. Org. Chem. 2006, 71, 8384. 13. Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561. 14. Sperry, J.; McErlean, C. S. P.; Slawin, A. M. Z.; Moody, C. J. Tetrahedron Lett. 2007, 48, 231. 15. Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13, 3356. 16. Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263. 17. Yamabuki, A.; Fujinawa, H.; Choshi, T.; Tohyama, S.; Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2006, 47, 5859. 18. Choshi, T.; Hibino, S. Heterocycles 2009, 77, 85. 19. Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Hieda, Y.; Nobuhiro, J.; Hibino, S. Heterocycles 2010, 82, 397. 20. Fujimoto, K.; Morisaki, D.; Yoshida, M.; Namba, T.; Hye-Sook, K.; Wataya, Y.; Kourai, H.; Kakuta, H.; Sasaki, K. Bioorg. Med. Chem. Lett. 2006, 16, 2758.