PSC 833,16 GF120918,17 LY335979,18 and VX-710.19 De-
spite these efforts, the mechanism by which Pgp binds a
broad spectrum of chemically unrelated compounds
remains unclear. Labeling studies have identified two
regions in each half of the protein within transmembrane
(TM)-5,6 and TM-11,12.20 An X-ray crystal structure has
been recently solved for an unbound bacterial form of
Pgp.21
A Mod ified Syn th esis of Iod oa zid oa r yl
P r a zosin
Merritt B. Andrus,* Sashikumar N. Mettath, and
Chun Song
Brigham Young University, Department of Chemistry and
Biochemistry, C100 BNSN, Provo, Utah 84602-5700
mbandrus@chem.byu.edu
Received J uly 19, 2002
Abstr a ct: The antihypertension agent iodoazidoaryl pra-
zosin (IAAP) has been made using a convergent route in-
volving addition of an acylated piperazine 7 to 2-chloroqui-
nazoline 5. IAAP has been shown to function as a multidrug
resistance (MDR) reversal agent and bind to P-glycoprotein,
a transmembrane transport protein. A study is also reported
involving palladium-catalyzed substitution with amine het-
erocycles. With N,N-bis(2,6-diisopropyl)dihydroimidazolium
chloride (10) as the ligand (2 mol %) for palladium(II) acetate
(2 mol %) in THF at room temperature, morpholine added
to 5 in 81% yield.
Iodoarylazido-prazosin (IAAP), a known antihyperten-
sion agent, was initially used by Gottesman to identifying
the two nonidentical Pgp drug-interaction sites and
continues to be employed as a standard photoaffinity
label for competition assays.22 Studies using IAAP to
further understand these binding issues are limited in
that only the radioactive form 125I-IAAP is commercially
available. The cost is prohibitive and its radioactivity
limits the nature of the experiments that can be done.
Because the synthesis of IAAP following the published
route23 proved to be unreliable and cumbersome, we now
report the synthesis of an improved, convergent route.
The key step involves a direct substitution reaction with
A major problem associated with cancer chemotherapy
is the emergence of drug resistance. Resistant cells show
increased expressions of P-glycoprotein (P-gp1)1 and the
multidrug resistance protein (MRP1).2 Resistance results
from the ability of Pgp to function as an ATP-dependent
efflux pump for various chemotherapeutic and cytotoxic
agents.3 Pgp is a 170 kDa membrane bound protein
comprised of 1280 amino acids and a 30 kD extracellular
carbohydrate domain consisting of two homologous halves
connected by a short linker region. Each half has six
transmembrane domains followed by consensus nucle-
otide binding domains which are catalytically active and
are required for transport function.4 Strategies to over-
come MDR involve the use of agents that bind Pgp and
inhibit its ability to extrude cancer drugs. These include
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10.1021/jo026217o CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/19/2002
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J . Org. Chem. 2002, 67, 8284-8286