Table 1. Antimicrobial Activities (MICs, µM) of Compounds
1-3
S.
B.
M.
E.
P.
compd
aureus
subtilis
smegmatis
coli
aeruginosa
1a
2b
3c
2.5
1.7
10.7
1.25
1.7
2.6
d
3.4
3.8
20
e
2.3
40
e
15.4
a Ref 4a. b Ref 5a. c Ref 5b. d Not evaluated. e No significant activity.
the attention of synthetic chemists and biologists alike,
benzylated flavanones are quite rare, and as such no efficient
syntheses of compounds related to 2 and 3 have been
reported.7 A straightforward synthesis would allow us to
evaluate the origin of their biological activity and prepare
analogues that may be more potent.
The substituent symmetry of 2 and 3 suggested that a
common core could be elaborated to provide both molecules.
The formation of benzylic carbon-carbon bonds with electron-
rich arenes is often achieved via ortho quinone methide
(OQM) intermediates, which can be accessed by a variety
of routes.8 Pinocembrin (4) could be converted to the OQM
precursor by benzylic functionalization (Scheme 1, path A).
Figure 2. Structures of synthetic (1) and naturally occurring (2
and 3) polyphenolic compounds.
one case, several compounds were demonstrated to disrupt
Z-ring formation.4a Zantrin Z1 (1, Figure 2), which was
discovered in a high-throughput in vitro screen for inhibition
of FtsZ GTPase activity,4 possesses a polyphenolic structure
reminiscent of several natural products that exhibit potent
antimicrobial activity. Dichamanetin (2) and 2′′′-hydroxy-
5′′-benzylisouvarinol-B (3), isolated independently by Huf-
ford and Anam from U. chamae and X. afticana respectively,
exhibited comparable MIC values to that seen with zantrin
Z1 when evaluated against a variety of bacterial strains.4a,5
It is notable that these compounds show a high level of
activity against Gram-positive bacteria (e.g. S. aureus, B.
subtilis; Table 1), and furthermore, the MIC values are
comparable to those of clinically relevant antibiotics.6
The structural similarity between polyphenolic compounds
1-3 suggested that they might all derive their antimicrobial
activity by inhibiting the GTPase activity of FtsZ. To test
this hypothesis, we undertook the syntheses of compounds
2 and 3. While naturally occurring flavanones have attracted
Scheme 1. Retrosynthetic Analysis of 2 and 3
(3) (a) Wang, J.; Galgoci, A.; Kodali, S.; Herath, K. B.; Jayasuriya, H.;
Dorso, K.; Vicente, F.; Gonzalez, A.; Cully, D.; Bramhill, D.; Singh, S. J.
Biol. Chem. 2003, 278, 44424-44428. (b) Reynolds, R. C.; Srivastava, S.;
Ross, L. J.; Suling, W. J.; White, E. L. Bioorg. Med. Chem. Lett. 2004, 14,
3161-3164. (c) White, E. L.; Suling, W. J.; Ross, L. J.; Seitz, L. E.;
Reynolds, R. C. J. Antimicrob. Chemother. 2002, 50, 111-114.
(4) (a) Margalit, D. N.; Romberg, L.; Mets, R. B.; Hebert, A. M.;
Mitchison, T. J.; Kirschner, M. W.; RayChaudhuri, D. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 11821-11826. The antibacterial activity of 1 was
first noted by Beaver: (b) Beaver, D. J.; Shumard, R. S.; Stoffel, P. J. J.
Am. Chem. Soc. 1953, 75, 5579-5581. After Beaver, Hakimelahi made
similar observations with 1 and related analogues: (c) Hakimelahi, G. H.;
Moshfegh, A. A. HelV. Chim. Acta 1981, 64, 599-609. (d) Moshfegh, A.
A.; Badri, R.; Hojjatie, M.; Kaviani, M.; Naderi, B.; Nazmi, A. H.;
Ramezanian, M.; Roozpeikar, B.; Hakimelahi, G. H. HelV. Chim. Acta 1982,
65, 1221-1228.
We initially planned to explore halomethylation, hydroxy-
methylation, and aminomethylation, since all of these pro-
cesses take place under neutral or acidic conditions. While
all of these processes are well-established for phenols, the
analogous transformations using resorcinols are almost un-
known.9 Furthermore, the base sensitivity of the flavanone
would limit the conditions that could be employed for the
formation of the OQM intermediate. An alternate synthetic
(5) (a) Hufford, C. D.; Lasswell, W. L., Jr. Lloydia 1978, 41, 156-160.
(b) Anam, E. M. Ind. J. Chem., Sect. B 1994, 33B, 1009-1011. See ref 4a
for MIC values of 1.
(7) The synthesis of gericudranin, a related p-hydroxybenzylated 3-hy-
droxyflavanone has been reported: Choi, Y.-J.; Shim, P.-J.; Ko, K.-S.; Kim,
H.-D. Heterocycles 1996, 43, 1223-1228.
(8) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367-
5405.
(9) (a) Tabatabai, M.; Vogt, W.; Boehmer, V. Tetrahedron Lett. 1990,
31, 3295-3298. (b) Tabatabai, M.; Vogt, W.; Baehmer, V.; Ferguson, G.;
Paulus, E. F. Supramol. Chem. 1994, 4, 147-152.
(6) The National Committee for Clinical Laboratory standards (NCCLS)
defines the effective MICs of methicillin, erythromycin, and vancomycin
as 0.8, 0.4, and 5.8 µM, respectively, against S. aureus. Higher MICs
indicate that a strain is becoming resistant to the drug. Leegaard, T. M.;
Caugant, D. A.; Frøholm, L. O.; Høiby, E. A. Clin. Microbiol. Infect. 2000,
6, 290-293.
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Org. Lett., Vol. 7, No. 25, 2005