SCIENCE & TECHNOLOGY

DRUG HYBRIDS
about how the hybrid version improves
the treatment’s efficacy. The hybrid may
increase cellular uptake, he says, noting

ENTER THE FRAY that the lipophilic artemisinin can have

problems getting into the cell’s aqueous
interior that the polar quinine can alleviate.
Combo molecules SURPASS COMPONENTS but “It’s easy to make water-soluble salts of the
combination,” Walsh adds.
sometimes work in unexpected ways Artemisinin also shows up in the hybrid
CELIA HENRY ARNAUD, C&EN WASHINGTON malaria treatments that the French compa-
ny Palumed is developing. These so-called
trioxaquines, first reported in 2000, com-
TWO DRUGS MAY BE BETTER than lege Dublin School of Pharmacy recently bine artemisinin and chloroquine moieties
one, especially if they are parts of a single combined fast-acting artemisinin and in a single molecule (ChemBioChem 2000, 1,
molecule. Hybrid drugs, just as their name slow-acting quinine into a hybrid drug for 281). Both drugs prevent the polymerization
implies, combine two drugs in a single mol- malaria, for which drug resistance is a bar- of heme into toxic hemozoin, but they act at
ecule with the goal of creating a chemical rier to effective treatment (Bioorg. Med. different stages in the parasite’s life cycle.
entity more medically effective than its indi- Chem. Lett. 2007, 17, 3599). Treatment with “The trioxaquine is able to alkylate
vidual components. These combo drugs can a fast-acting malaria drug by itself can lead heme like artemisinin does, while the
indeed be more powerful than either of their to reoccurrence of the parasite Plasmodium quinoline entity is able to interact with free
precursors, and for
reasons that aren’t
SURPRISE This aspirin-NO donor hybrid doesn’t behave as expected. After hydrolysis, the fragment
always what the drug
containing the spacer and the –NO3 group undergoes a 1,6-elimination to form quinone methide.
developers expect.
Most tantalizing
O ONO2 O
are hybrids that are
much better than O Hydrolysis OH ONO2 –NO3
their respective +
building blocks. O O HO O
“Just by combining
O O Quinone
two molecules in methide
the proper way, you
sometimes have
an activity increase of a factor of 100 or falciparum, which causes the disease. But if heme and block the polymerization,” says
1,000,” says Michael Decker, a medicinal in addition “you have a slow-acting antima- Bernard Meunier, a pioneer of antimalarial
chemist at the Institute for Pharmacy at larial agent like quinine, there’s a chance hybrids and now chief executive officer of
Friedrich Schiller University, Jena, in Ger- that it will kill the remaining parasites that Palumed. The trioxaquines are the furthest
many. Although they are often combina- haven’t been killed by the fast-acting anti- advanced of the antimalarial hybrids. One
tions of approved drugs, no hybrid drugs, malarial agent,” Walsh says. of Palumed’s compounds is in preclinical
which from a regulatory perspective must Walsh and his coworkers connect the development at Sanofi-Aventis and is ex-
be treated as new chemical entities, have two drugs with a linker no more elaborate pected to enter clinical trials in early 2009,
themselves been approved as drugs. than an ester bond. “We were very careful according to Meunier.
A major driving force in the hybrid drug to ensure that the activity of each molecule
development community is to overcome wasn’t compromised by the site at which THE ANTIMALARIAL hybrid designed by
one of the worst things that can happen to the two were linked together,” Walsh says. David H. Peyton, a chemistry professor at
a drug: the development of resistance in its Ester derivatives of artemisinin, such as the Portland State University, in Oregon, com-
target population. In most such hybrids, drug artesunate, don’t adversely affect the bines the drug chloroquine with a so-called
the two druglike portions, also called phar- parent drug’s antimalarial activity, he notes. reversal agent, which counters resistance
macophores, have independent modes of In vitro assays show that the hybrid is and is based on the antidepressant imip-
action that make the emergence of drug more effective against drug-sensitive and ramine (J. Med. Chem. 2006, 49, 5623). The
resistance less likely. drug-resistant malaria than the individual reversal agent inhibits a membrane chan-
Chemist John J. Walsh, biologist Angus drugs alone or a cocktail made of a 1:1 molar nel that pumps chloroquine out of the par-
Bell, and coworkers at the Trinity Col- ratio of the two. Walsh has several guesses asite’s digestive vacuole, the drug’s site of
action. The hope is that most of the hybrid
molecules will continue to do what chloro-
“Just by combining two molecules in the quine alone usually does—bind heme and
prevent the formation of hemozoin—and
proper way, you sometimes have an activity that the remaining hybrid molecules will
take on the role of blocking the parasite’s
increase of a factor of 100 or 1,000.” membrane pump.

WWW.C E N- ONLI NE .ORG 46 NOV E M BE R 1 2 , 20 07

 Featured Topic Issues
Bioavailability of Chemopreventive Flavonoids and Polyphenols
Volume 4, Issue 6, November/December, 2007
Guest Editor: Ming Hu, Ph.D. Department of Pharmaceutical Sciences, College of Pharmacy, University of Houston
“This issue highlights the methodologies that can be used to assess the bioavailability of flavonoids and polyphenols. More bioavailable or
highly bioavailable polyphenol formulations or derivatives are very desirable because they will be easier to develop and less costly to test.
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Ming Hu (Editorial)
Bioavailability of Curcumin: Problems and Promises
Preetha Anand, Ajaikumar B. Kunnumakkara, Robert A. Newman, and Bharat B. Aggarwal
(Review)
Biotransformation of Green Tea Polyphenols and the Biological
Activities of Those Metabolites
Joshua D. Lambert, Shengmin Sang, and Chung S. Yang (Review)
Methylation of Dietary Flavones Greatly Improves Their Hepatic
Metabolic Stability and Intestinal Absorption
Thomas Walle (Review)
Intestinal and Hepatic Glucuronidation of Flavonoids
Li Zhang, Zhong Zuo, and Ge Lin (Review) Antigen Pharmaceutical
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Volume 4, Issue 1 Volume 4, Issue 3
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UDP-Glucuronosyltransferase (UGT) Isoforms Responsible for the
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Xing Liu, Vincent H. Tam, and Ming Hu (Article)
Pharmacokinetics and Bioavailability of the Bioflavonoid Biochanin A:
Effects of Quercetin and EGCG on Biochanin A Disposition in Rats
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Disposition of Flavonoids via Enteric Recycling: Enzyme Stability Affects
Characterization of Prunetin Glucuronidation across Species, Organs,
and UGT Isoforms
Tiby B. Joseph, Stephen W. J. Wang, Xing Liu, Kaustubh H. Kulkarni, Jingrong Wang,
Haiyan Xu, and Ming Hu (Article)
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The best of Peyton’s hybrid drugs, called
reversed chloroquines, are about 10 times
more effective against drug-sensitive malar-
ia than chloroquine by itself. Adding to this
hybrid’s promise is its ability to kill a chloro-
quine-resistant strain of P. falciparum.
Peyton believes that the hybrid has an
advantage over a simple cocktail of the
two drugs. In a cocktail, the reversal agent
is unlikely to make it into red blood cells
where the malaria parasites live, he says.
In the hybrid, the reversal agent tags along
with the chloroquine into the cells and
then all of the way to the parasite’s diges-
tive vacuole. “If you do it as a cocktail, you
figure out what gives one such aspirin-nitric
oxide hybrid its antitumor properties. In
this hybrid, the aspirin and nitrate are con-
nected by a simple aromatic spacer.
The researchers lopped the pharmaco-
phores off the hybrid one at a time, leaving
the linker in each case. When they removed
the aspirin moiety, the remaining portion of
Reversal agent
Chloroquine-like portion
portion
CH3
HN N
N

need a much greater dose of the reversal Cl N

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agent” to get the same effect, he says.

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Despite hybrids’ promising properties

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and seeming advantages, a clear picture of
how they achieve their effect is difficult to
come by. The individual components may
not have the same mode of action in the
hybrid that they do as separate molecules.
meant to be a simple three-month under-
remain connected in the living system is
difficult.
The chemical bridge linking the two
pharmacophores adds new dimensions to
the drug developer’s task. To keep the phar-
macophores together, for example, the link-
er needs to withstand oxidation reactions in
the cell that would other-
wise sever the connection,
Meunier says. “If you have
fast oxidation or hydroly-
sis of the linker, then you
get just the release of two
drugs and it’s more or less
a prodrug approach.”
THE LINKER itself can
even end up exerting a
greater effect on the activi-
ty of the combination than CH3O
people assume or original-
ly hoped. A recent example
of a hybrid that combines
Artemisinin-quinine hybrid
aspirin and a nitric oxide
Reversed chloroquine
the hybrid was still very active. “Our curiosi-
ty was triggered,” Wijtmans says. Something
graduate project stretched out to 18 months.
Eventually, he and his colleagues discovered
to their surprise that the hybrid molecule’s
anticancer properties came from neither
pharmacophore (J. Med. Chem. 2007, 50,
2424). “We chopped off both presumed
pharmacophores and got a compound that
was 10 times more active,”
Wijtmans says.
The nitrate part of the
O
hybrid gets little chance
O O to act as the nitric oxide
O donor it was designed to
be. The hybrid is quickly
O hydrolyzed to aspirin and
another fragment consist-
O ing of the spacer and the
HO N nitrate. This second frag-
ment rapidly eliminates
the nitrate to yield cytotox-
ic quinone methide. With
N this antitumor hybrid, the
spacer turned out to be the
active component.

donor is a case in point. “In the end, the func-

Aspirin is well-known to have many ben-
eficial effects. Unfortunately, high doses
can cause stomach problems. Because ni-
tric oxide can block that toxicity, combin-
ing aspirin and NO in one molecule could
provide the benefits of aspirin without its
nasty side effects.
Postdoc Maikel Wijtmans of Free Uni-
versity, Amsterdam; undergraduate Niels
Hulsman of Free University and the Univer-
sity of Amsterdam; and coworkers set out to
tion of the nitrate group was as a leaving
group, while aspirin served only as a pas-
sive cap for the spacer,” Wijtmans says.
“The take-home message is that people
should consider carefully what spacer they
use” when designing hybrid drugs.
Perhaps that shouldn’t be so surprising.
After all, however familiar the building
blocks may be, hybrid drug molecules are
at their core new molecules, with identities
independent of their precursors. ■

WWW.C E N- ONLI NE .ORG 48 NOV E M BE R 1 2 , 20 07