Synthesis and biological evaluation of manzamine analogues

Article abstract of DOI:10.1021/ol061320b

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

Full text of DOI:10.1021/ol061320b

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3407-3409
Synthesis and Biological Evaluation of
Manzamine Analogues
Jeffrey D. Winkler,* Allyn T. Londregan, Justin R. Ragains, and Mark T. Hamann*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104, and Department of Pharmacognosy,
UniVersity of Mississippi, UniVersity, Mississppi 38677
winkler@sas.upenn.edu
Received May 30, 2006
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.
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 anti-
malarial agents with new mechanisms of action are needed
as monotherapeutic agents and for use in combined chemo-
therapy 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 avail-
able 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-â-carboline-containing manzamine
congener ircinol A (2)5 prompted us to leave the â-carboline
heterocycle intact in all new analogues.
(1) Marshall, E. Science 2000, 290, 428-430. (b) Marshall, E. Science
2000, 290, 437-438. (c) Bell, A. I. Drugs 2000, 3, 310-317. (d) Newton,
P.; White, N. Annu. ReV. Med. 1999, 50, 179-192. (e) Bell, A. Curr. Opin.
Anti-Infect. InVest. Drugs. 2000, 21, 63-70.
(2) Sayed, El; Kelly, M.; Kara, U.; Ang, K.; Katsuyama, I.; Dunbar, D.;
Khan, A.; Hamann, M. J. Am. Chem. Soc. 2001, 123, 1804-1808.
(3) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425-
6426.
(4) Humphrey, J. M.; Ali, A.; Hillier, M. C.; Martin, S. F. J. Am. Chem.
Soc. 1999, 121, 866-867.
10.1021/ol061320b CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/29/2006

which results from the regiochemistry of enolization of the
ketone precursor, is regioisomeric with the ∆10,11 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.
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
Scheme 2. ABCE Synthesis
Figure 1. Analogues targeted for synthesis.
We prepared the B ring analogue 6 via Suzuki coupling
of known boronic ester6 7 and 1-bromo-â-carboline.7 The
corresponding AB and BC ring analogues 5 and 4, respec-
tively, could be constructed in a similar manner via the
Suzuki coupling of the appropriate BC and AB boronic
esters8,9 with 1-bromo-â-carboline (Scheme 1). We note that
the ∆9,10 alkene in â-carboline 10 (manzamine numbering),
unsaturated ester 12 was effected via carboxylation of the
enolate derived from 11 to give the corresponding â-
Scheme 1. B, BC, and AB Ring Synthesesa
(5) Ang, K. K. H.; Holmes, M. J.; Higa, T.; Hamann. M. T.; Kara, U.
A. K. Antimicrob. Agents Chemother. 2000, 44, 1645-1649.
(6) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem.
Soc. 2002, 124, 8001-8006.
(7) Bracher, F.; Hildebrand, D. Tetrahedron 1994, 50 (43), 12329-12336.
(8) The AB boronic esters were synthesized starting from commercially
available 5-hydroxyisoquinoline. Hydrogenation of 5-hydroxyisoquinoline
(Adams catalyst, HOAc, H2SO4) followed by Boc-protection of the crude
amine afforded a mixture of diastereomeric alcohols (48%). The cis- and
trans-alcohols were separated chromatographically and then oxidized with
Dess-Martin reagent to the corresponding cis- and trans-fused ketones (71
and 55%, respectively). The separated ketones were then converted to the
corresponding enol triflates (KHMDS, Comins’ reagent) to afford 68 and
72% yields of the cis- and trans-enol triflates corresponding to 8,
respectively. The enol triflates were then converted to the corresponding
boronic esters using the method of Miyaura7 (bis-pinacolatodiboron, PdCl2-
(PPh3)2, PPh3, PhMe) to afford 91 and 78% yields of the cis- and trans-
boronic esters 8a and 8b, respectively.
(9) The BC boronic ester 9 was synthesized starting from commercially
available 5-hydroxyindole, which was hydrogenated (Rh/Al2O3), followed
by Boc protection of the resulting crude amine (48% overall yield). The
resulting epimeric alcohols were oxidized with Dess-Martin reagent to
afford the corresponding cis-fused ketone as a single diastereomer (74-
99%). The ketone was then treated with KH at room temperature followed
by the addition of Comins’ reagent (72%) to afford the ∆9,10 (manzamine
numbering) enol triflate, which is iomeric with the ∆10,11 alkene regio-
chemistry in the B ring of manzamine A (72% yield). Attempts to generate
the (∆10, 11) enol triflate under kinetic conditions resulted in the formation
of inseparable mixtures of regioisomeric enol triflates. Conversion of the
iso-BC enol triflate to boronic ester 9 was achieved via the aforementioned
method of Miyaura.
(10) Winkler, J. D.; Axten, J.; Hammach, A. H.; Kwak, Y.; Lengweiler,
U.; Lucero, M. J.; Houk, K. N. Tetrahedron 1998, 54, 7045-7056.
(11) Peng, J.; Shen, X.; El Sayed, K.; Dunbar, D.; Perry, T.; Wilkins,
S.; Hamann, M.; Bobzin, S.; Huesing, J.; Camp, R.; Prinsen, M.; Krupa,
D.; Wideman, M. J. Agric. Food Chem. 2003, 51, 2246-2252.
a For the preparation of 8 and 9, see footnotes 8 and 9.
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Org. Lett., Vol. 8, No. 15, 2006

ketoester, followed by ketone reduction and â-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. Bis-
chler-Napieralski cyclization of 13 followed by DDQ-
mediated dehydrogenation afforded the Boc-protected ABCE
analogue 14. Boc deprotection followed by reductive alkyl-
ation 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 attenu-
ated 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.
One of us has recently described the isolation of manz-
amine 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 manz-
amine A are currently underway in our laboratory, and our
results will be reported in due course.
Table 1. Evaluation of Analogues Against P. falciparum
Acknowledgment. We gratefully acknowledge the gener-
ous financial support of the NIH, GlaxoSmithKline, Merck,
Amgen, Wyeth, and Boehringer-Ingelheim.
W2 clone IC50
(ng/mL)
D6 clone IC50
(ng/mL)
compound
manzamine A (1)
B (6)
iso BC (10)
cis AB (5a)
trans AB (5b)
ABCE (14)
13.5
5550
4190
1270
2770
520
25.0
3510
920
930
1020
270
Supporting Information Available: Experimental pro-
1
cedures and H 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.
OL061320B
Org. Lett., Vol. 8, No. 15, 2006
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