B. Quinolines and Their Derivatives
Multidrug resistance poses an increasingly important problem for
chemotherapy. Several compounds, zosuquidar (Chapter 4) and biriquidar
(Chapter 6), that attempt to overcome this by interfering with the mechan-
ism by which cells extrude drugs were noted earlier. A compound that
includes in its structure both a quinoline and a perhydroisoquinoline
moiety shares the mechanism of action with its predecessors. The per-
hydroisoquinoline moiety ( 31 ) can conjecturally be prepared by alkylation
of 28 with the chloroethyl nitrobenzene ( 29 ). Catalytic hydrogenation of
the product ( 30 ) would then reduce the nitro group to afford intermediate
31. Acylation of the newly formed amine with the nitrobenzoic acid ( 32 )in
the presence of cyclohexyl-morpholino-carbodiimide then yields amide
33. Hydrogenation again converts the nitro group to the corresponding
aniline ( 34 ). Acylation of intermediate 34 with quinoline-3-carboxylic
acid ( 35 ) yield the extended antharanilamide. Thus tariquidar ( 36 )
is obtained.^7
NHCH 3 O
CH 3 OCl
NO 2+CH 3 O
CH 3 O N
NR 2
HO 2 C
O 2 NR 2 NCH 3 OCH 3 O N
NHOOCH 3
OCH 3OCH 3
OCH 3NCO 2 HNOHNCH 3 O
CH 3 O N
NHO
OCH 3
OCH 328 29 3130 ; R = O; R = H3233 ; R = O
34 ; R = H3536As noted in Chapters 4, 5, and 7, compounds aimed at disrupting
tyrosine kinases have been intensively studied as potential antitumor
compounds. The quinoline-based inhibitorpelitinib( 45 ) incorporates a
Michael acceptor function in the side chain that can form a covalent
bond with a nucleophile on the target enzyme. Such an interaction
would result in irreversible inhibition of the target kinase. Reaction of
the aniline ( 37 ) with DMF acetal leads to the addition of a carbon
atom to aniline nitrogen in the form of an amidine ( 38 ). This intermedi-
ate is next reacted with nitric in acetic acid to form the nitrated product
- COMPOUNDS WITH ONE HETEROATOM 167