Abstract
The synthesis and biological evaluation of a series of analogues of manzamine A, representing partial structures of the pentacyclic ABCDE diamine core, is described. All new compounds were screened against Plasmodium falciparum and demonstrated attenuated antimalarial activity relative to that of manzamine A.
Graphical abstract
Malaria is a disease that affects 300–500 million people each year and results annually in 1–2 million deaths, mostly among children. Structurally and functionally novel antimalarial agents with new mechanisms of action are needed as monotherapeutic agents and for use in combined chemotherapy with other presently available drugs. The urgent need for new and effective antimalarials escalates as Plasmodium falciparum and other human malaria parasite species have developed resistance to most of the commercially available antimalarials.1 The manzamine alkaloids represent important lead structures for the development of anti-infectives. Manzamine A and related structures are highly potent, orally bioavailable2 antimalarial agents that are more effective than most currently available therapeutics, i.e., chloroquine and artemisinin. In addition, some of the manzamine class have also demonstrated activity against the AIDS-opportunistic infectious diseases including tuberculosis and toxoplasmosis.
The isolated yield of 1 from its natural source, the Okinawan sponge Haliclona sp., was originally reported to be 0.026% from wet sponge. The paucity of 1 from the natural source, coupled with the length of the total syntheses reported from our laboratory and by Martin,3,4 prompted us to examine the biological activity of simplified structures based on 1. We report herein the design, synthesis, and preliminary biological evaluation of a series of analogues of the pentacyclic ABCDE diamine core of manzamine A (Figure 1). The ca. 400-fold dimunition in activity against P. faciparum for the non-β-carboline-containing manzamine congener ircinol A (2)5 prompted us to leave the β-carboline heterocycle intact in all new analogues.
Figure 1.
Analogues targeted for synthesis.
We prepared the B ring analogue 6 via Suzuki coupling of known boronic ester6 7 and 1-bromo-β-carboline.7 The corresponding AB and BC ring analogues 5 and 4, respectively, could be constructed in a similar manner via the Suzuki coupling of the appropriate BC and AB boronic esters8,9 with 1-bromo-β-carboline (Scheme 1). We note that the Δ9,10 alkene in β-carboline 10 (manzamine numbering), which results from the regiochemistry of enolization of the ketone precursor, is regioisomeric with the Δ10,11 B-ring alkene in 1. Completion of the synthesis of cis-AB 5a, trans-AB 5b and iso-BC 10 analogues was achieved by Boc deprotection of the Suzuki adducts and reductive alkylation of the resulting secondary amines with propionaldehyde.
Scheme 1.
B, BC, and AB Ring Synthesesa
a For the preparation of 8 and 9, see footnotes 8 and 9.
The preparation of the ABCE analogue 3 is based on our total synthesis of 13 and proceeds through the tetracyclic ketone 1110 (Scheme 2). Regioselective conversion of 11 to unsaturated ester 12 was effected via carboxylation of the enolate derived from 11 to give the corresponding β-ketoester, followed by ketone reduction and β-elimination of the derived mesylate. Coupling of the carboxylic acid derived from 12 with tryptamine in the presence of BOP (Castro’s reagent) led to the formation of amide 13. Bischler–Napieralski cyclization of 13 followed by DDQ-mediated dehydrogenation afforded the Boc-protected ABCE analogue 14. Boc deprotection followed by reductive alkylation with propionaldehyde afforded the ABCE tetracycle 3. The B, AB (cis and trans), iso-BC, and ABCE analogues were then screened for activity against the W2 and D6 (chloroquine-resistant) clones of P. falciparum (Table 1). Two features of these data are striking: (1) the relatively narrow range of differences in biological activity among the new monocyclic (B), bicyclic (AB and BC), and tetracyclic (ABCE) analogues (ca. 101) and (2) the significantly attenuated activity of all new analogues relative to manzamine A (ca. 103). These results suggest that partial structures of manzamine A may not serve as useful leads for the development of new anti-infectives.
Scheme 2.
ABCE Synthesis
Table 1.
Evaluation of Analogues Against P. falciparum
| compound | W2 clone IC50 (ng/mL) |
D6 clone IC50 (ng/mL) |
|---|---|---|
| manzamine A (1) | 13.5 | 25.0 |
| B (6) | 5550 | 3510 |
| iso BC (10) | 4190 | 920 |
| cis AB (5a) | 1270 | 930 |
| trans AB (5b) | 2770 | 1020 |
| ABCE (14) | 520 | 270 |
One of us has recently described the isolation of manzamine A and related substances in significantly higher yield than originally reported, making 1 a viable starting material for the development of new chemotherapeutic agents.11 Studies directed toward the development of new malaria chemotherapy lead structures via functionalization of manzamine A are currently underway in our laboratory, and our results will be reported in due course.
Supplementary Material
Acknowledgments
We gratefully acknowledge the generous financial support of the NIH, GlaxoSmithKline, Merck, Amgen, Wyeth, and Boehringer-Ingelheim.
Footnotes
Supporting Information Available: Experimental procedures and 1H NMR, 13C NMR, and FT-IR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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