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ACS Medicinal Chemistry Letters
ICT, isocyanoterpene; TMEDA, tetramethylethylenediamine;
TFAA, trifluoroacetic anhydride; TMS, trimethylsilyl; TBS, tert-
butyldimethylsilyl; TBAF, tetra-n-butylammonium fluoride.
serious structural changes relative to the natural kalihinols and
1
2
3
4
5
6
7
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in spite of its racemic nature. This compound was subjected to
microsomal stability assays, using both human and murine
liver microsomes. Interestingly, we found that this potent ICT
analogue showed significant stability in the presence of liver
microsomes, with half-lives of 142 min (human) and 87 min
REFERENCES
1. Fernández-Álvaro, E.; Hong, W. D.; Nixon, G. L.; O’Neill, P.
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4. Only a select few of the over 50 kalihinane natural products have
been evaluated in antimalarial assays, reflecting the relatively late
discovery of this activity relative to the isolation of many of these
compounds.
5. Antimalarial activity of kalihinol A and four other kalihinanes:
Miyaoka, H.; Shimomura, M.; Kimura, H.; Yamada, Y.; Kim, H.-S.;
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Functionalized Diisocyano Diterpenoid Antibiotic from a Sponge J.
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Winzeler, E. A.; Shenvi, R. A. Synthesis of (+)-7,20-
Diisocyanoadociane and Liver-Stage Antiplasmodial Activity of the
Isocyanoterpene Class J. Am. Chem. Soc. 2016, 138, 7268–7271.
8. Daub, M. E.; Prudhomme, J.; Le Roch, K.; Vanderwal, C. D.
Synthesis and Potent Antimalarial Activity of Kalihinol B J. Am. Chem.
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9. In their investigations on the kalihinols, the Wood group made a
large number of analogues based on the cadinane, or “truncated kali-
hinane” framework. They synthesized five isonitrile-containing com-
pounds, including (±)-15 (10-isocyano-4-cadinene) and (±)-22. Others
were made that bore isothiocyanates and formamides in the usual
positions of the isonitriles; these functional groups have also been seen
in natural products co-isolated with ICTs. Further analogues were
made with nitriles and azides. None of the compounds devoid of isoni-
triles demonstrated appreciable antimalarial activity, See refs 10, 11,
and 12.
10. White, R. D. Ph.D. Dissertation, Yale University, 2003.
11. Keaney, G. F. Ph.D. Dissertation, Yale University, 2005.
12. White, R. D.; Wood, J. L. Progress toward the Total Synthesis
of Kalihinane Diterpenoids Org. Lett. 2001, 3, 1825–1827.
13. Chi, Y.; Gellman, S. H. Diphenylprolinol Methyl Ether: A
Highly Enantioselective Catalyst for Michael Addition of Aldehydes
to Simple Enones Org. Lett. 2005, 7, 4253−4256
24
(murine). While more studies are warranted, this preliminary
result suggests that there is nothing intrinsically poor about the
salient isonitrile functional groups that are so intimately tied to
potency in the ICT family of antimalarials.
9
The kalihinol scaffold appears to be a promising starting
point for the development of interesting antimalarial lead
compounds. Many of the simplified analogues synthesized in
this study retain high potency and are much easier to access
than the natural products; however, the results do not show
clear SAR trends. The ICTs have been shown previously to
show good selectivity indices3,5 with respect to mammalian
cytotoxicity and to have multi-stage activity;7 the latter point
conflicts previous notions that their activity is due to inhibition
of pathways for heme detoxification.25 We have now shown
that the salient isonitrile functional groups are not a metabolic
liability. Future studies aimed to engineer the kalihinane scaf-
fold to identify simpler congeners with improved physico-
chemical properties and high in vitro and in vivo efficacy are
warranted, as are investigations into the incompletely under-
stood mechanism(s) of action of these antimalarial agents.
10
11
12
13
14
15
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17
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21
22
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34
35
36
37
38
39
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47
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ASSOCIATED CONTENT
Supporting Information
In the associated PDF, we include general experimental details,
experimental procedures for the synthesis of and characterization
data for all new compounds. Experimental details and raw data
for the antimalarial assays and information about the metabolic
stability experiments for compound (±)-37 are also provided.
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
Author Contributions
The manuscript was written through contributions of all authors.
Funding Sources
CBM’s research is supported by NIH (AI123321; AI097218;
GM110506; AI09486; AI119691) and The Bill and Melinda
Gates Foundation (1021571) grants.
This study was financially supported by the University of Califor-
nia, Riverside (NIFA-Hatch-225935 to KGLR). The funding
body had no role in the design of the study, in collection, analysis,
and interpretation of data, or in writing the manuscript.
MED was supported in part by an Allergan Graduate Fellowship.
14. Chen, K.; Ishihara, Y.; Galán, M. M.; Baran, P. S. Total Syn-
thesis of Eudesmane Terpenes: Cyclase Phase Tetrahedron 2010, 66,
4738−4744.
15. Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Stereoinversion of
Tertiary Alcohols to Tertiary-alkyl Isonitriles and Amines Nature
2013, 501, 195–199.
16. Okino, T.; Yoshimura, E.; Hirota, H.; Fusetani, N. New Anti-
fouling Sesquiterpenes from Four Nudibranchs of the Family Phyllidi-
idea Tetrahedron 1996, 52, 9447–9454.
17. Nishikawa, K.; Nakahara, H.; Shirokura, Y.; Nogata, Y.; Yo-
shimura, E.; Umezawa, T.; Okino, T.; Matsuda, F. Total Synthesis of
10-Isocyano-4-cadinene and Determination of Its Absolute Configu-
ration Org. Lett. 2010, 12, 904–907.
ACKNOWLEDGMENT
The following reagents were obtained through the MR4 as part of
the BEI Resources Repository, NIAID, NIH: Plasmodium falciparum
strains 3D7 (MRA-102) deposited by D.J. Carucci and Dd2
(MRA-156) deposited by Thomas Wellems.
18. Nishikawa, K.; Nakahara, H.; Shirokura, Y.; Nogata, Y.; Yo-
shimura, E.; Umezawa, T.; Okino, T.; Matsuda, F. Total Synthesis of
10-Isocyano-4-cadinene and Its Stereoisomers and Evaluations of
Antifouling Activities J. Org. Chem. 2011, 76, 6558–6573.
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