Bioreductive antineoplastic agents: a new approach to the treatment of solid tumors.

K",)+R/I! RF!$F;!/../

eL 'C[( RR(#4R

% &,(%&,+&0;V(+0("+0..,1*+($%&0*%%;,.&%,+*%%.%0,.%,%$&,0 ,$0.((-;+0(

.A"A 0

"5 G(! * ( 9 % ! > !0R0V ! FF/$! :/$..:D7

.A9R%B

G(>9(!>(>1! > !0R41!/F.!.:.::/ D7

E:$ZZ.:_/$Z/Z./

D*E"*+0 * -@0*0 L0 T0--E077E0 >@*"ER05 # ( &5C & 5 # ( (55( & R ( #2(C &C5% & '4 C 4 C C &&5( 4 R 7Q! & &C5% %5 # &5C C % &C5% 5(4 R D( (4 2( (4C% R& 5 #C555( &Q%C4 5 ( R&(2(5 #&C5% &(( 5 54# &5CR

UCQ L (_&C5% _(5(4 R

+&,.0'/0

( < ( ! 5( 2(45# <=#<=( R0 ( 2( # # <=51 5#% #(

2(55( (( B :_R

-4 5 2(5 # 4 14((!2(#(!B( <=( ( ! 5<= 2(15 5B #1 R ( ( M% 5 (# 5# (! 23! M % (( 2( 5

=/_{R ! 5 4 &( 2(!}

(! = ( 2(15 ! #23! ( ! = 2( 2( 5 ( 5 4 ( 5 =R ( M ! 2( 5 =(! 5(=!M! ( .\ 5 &R 5 5 !4! 55( 4 2(15 % (!(2(2(( 59( )(4!5!2(5!(5#5 ,( <= !%

#_{R0 !((<=2(5}

2( #1 51 M%5

5 %(/!;_R

%.%,.1(,+%(0(,$0.((-;+0(

0155<=55(! ((((= ! 5 !(4(

5#<=R0 ( 51 #23(5 ( (R 43 2( < (5&::.\( (R 5< 5&514 N N2( ( 51 5 51 (<=I_R

*! 43( (<= % 4=R "( (! 4( 43 5% = ( ( 5 R- !52( 43 < (4) (<=, # % ! = ( 4(<O 5 R 23!4( 1 ( =4 !( 95((&( (<=!2(#2(5%49( 5 4( 4O ( B( #2( R0 ( 5M% 43 )5# (, = ( %4 R0 ( ( ! 5! (<=! = ( M% M R>! ( % ( 4O =& ( &5M%!5 =

(4=%<=%49)>4(:,I_R

._RX :

2( ( %4<= = # <=2( ( <O &5M%R * 52( ( _/ 4 5 5( 5<=!4

! 5%)Ez,!

&%)7z, (5M%) /

z_{,!2(5 (<=}

( 23(:.!::_R-!

( ( &5M% 4O % <=%49! ( %

$$ 04 051 D(

EN,G

# 2(%5 9 ( M J 2(5#(#1< ( &5M%R42(151 5 4(< ( &5M%<O 59( L:,4 43 (_/, 5 <= ,#(5 <=J ( &5M%)>4(/,I!F!_R

0 ! ( &5M%!5 5 !5 (545

#5( )# _.,;!:;_{R-!5 52(}

B 4 2(15 ( (!(2( =! (! #1 2(# =((!55!

( 15 =;_R

% &,(%&,+&0;V(+0("+0..,1*+(

:$/! :I_&5M

2( ( &5M% 5 5 5 (<= 2( ( %4 R > 55 ! =!2( ( &5M%5 % 5 4 51 ! 2( M M% 5M <= M 5

( ( :I_{R 4 51 ( =}

5M#1 ! # 5( R 5(

= ( )5M#1 , 2(! ))! #

<=! 4 5 % (!

4J( ( #)#1,:F!:$_L

^ 8!

9 55 =#( 5 ( 4 51 5( &5M%L ( #( 2( !(<= 5 4O ( &5M%5 5

( :_R

<= 55 5 4 2( ( (42(<=2( (

5 ( 5 (<=:!:_{R ( 9 (4}

2(!5 5 1 !#%5

(<=V)_:Z/0 _/Z0 _/z_,

N;..N/..+) 7!5M!57$)I%:.

5= # #,:!/._{R - )) = 1}

(5( :_R

!

<=( ( ( &5M% % (!I$!!:.!:/:I!:/I ₉ 55 =& R05 M

(#(<=2(! 2( )F,

5M5/:_R

0 4( M ! 2( # ( ! 2(5 %5#5( &5M%R 55 5

=)H, )U,:._R

0 ,M% !5

5 5 ):!;,M%:!/!;

!E;/,)T,/I_R

/"0 A5)""<""A5

A5'2"A5c\6O6 82 SQ

/"$$?6%))6A

G( 5 5<O 2( ( (( 5 ( ( 2( 1 ( # I.R0 5 <= 2( = 0"-7L -;I. ( 0")-,7L2( %( )"# ,/F_R

0)F,# !5T'' !

(( 6"+6:I/$_RG( )>4(, =4(R =M # 5 4 !

)F, 5# )K, 5

(/F_R

+1 & 9 2( <= (

)F, (#<=1 2(

4 0" 5 4<O ( ( #

5 )4<=#,/!/_{R 2(<=}

M4)F,5M (<=V!

#<=(!((<=V!

#<=&2( 5/;!/_{R0 1}

(<= )F,! 5

>4(;!5 2(49&5 ( 1 49 J B(4<= 5 =4492(R !5M #(<=! 495 ( 1!5 5(## !=!%5( =4(5%R05 ( 5 ! (#<= 5

5 1 5)F,:$!._R

0)F, (2(5

1 5 ( M ! (( = # ! (5 =

4 /F_{R= !1 14}

)F,9 ( (%(

#1:;_R

05#)K,#5 ( ( (

J 4 % 5 (

&5M%I_{R0 ( 5# )}K_,

( :F$F_{R0(! # ***}

4! <=5!

( 5 <$_R05

#15#)K,<=J)F,!

(( 5 (5 =2(5 /F_R

/"+!?"""SC

$ 04 051 D(

EN,G

)L,!(2(14J)F,!#

:$ _{(( %}

(!;._R

)L, 5 <=

)F,R #%5 =4

49 2(R05M (<=! 49 (!#! !5<=1! (( 5#52( 0" :$!._)>4(I,R

0(<=)L,!#(!

5J<=(( ( &% M !5

%5!5# #<=))! ( 5 2(

5 #( 0" ;._{R (}

B ;:_{!5! (}

( # **4=##1 5 = (! V4!

5 !M5(=;/_R!)L_,=#

<= 5 ( 4 51 <= ( ( M R

#5 5 15#)L,#

5 ( !B12( 5 % 5 ( ( &5M% 5 = 5

( <O ;_R

0 ( M >E..;/ )G,>EFF$)FI,! (( 6"+!

((5 5;;_{R (}

5 !>E..;/)G, (>U

$)FF,#9 5 2()F,!

5 %.!;I!;F_R

05 #(<=2(= 5 ( ((! M ( 5 ( (

()F,2((<=5

% (.!;;;$_{R> 2((<=} M =J#<= (5M% #

5%5%%5 5 ( ._R

(<=)G,)FF,!5!

(<=4<= &%&1!# 5 >4(F;$_R

&6

#F.!0 !>Q # 5 (<=5 #V )4 # 5<=,5( &5M%R 5

5 # %49;_{R (}

( M ( )H,

/"4 )A5);MBBDUEO6QDT

##<=))2(&5M ;_{R 5 #} ! !5 !# 2( %5 <= 54 ( &5M% 1 ( ( !

( 9<=I._{R* J(<=M}

1 1 ! 2( 55 5 1 5<=M% =

E _/z_{&%E 77}I.!I:_{R0 2(}

E _/z_{7(5 )(E}

/ z

5 5M ,!%0"

239(5( (<=(5&1(I:_R

<=J&%!U% 55( 2( 5 5 40" J (<= )) ( 23<=,M%0" I/!I_R <= 5 (<= M 5

5 #>4($I;_R

- !51 >4($!2(5 <%49 5(55(<=R ( &5M%<=%49(!5 5(<= #! (# <=1 R 9# 5 ( (

157;_R

05 M ! )H,

)U,!5 ( 5( &5M%!

5 %59! 23! =

1 5%(<=M%III_R#(<=

! 5 = ( R14

)E:.F,)FH,# (2(5 <

(4(52(!!5( (

59 5 I_R

E :.F )FH, = 5 ( (

%2( )U,! (

5 ( &5M%)cI.:.. ,I$!F._R

% 5 <O 2(<=0" 5R ( (4#(( M%54 <=(0" )>4(,R*#! (

4E:.F)FH,#

%4 2(5 (5 4( ( I$!F._R

! #5(5M#1 E :.F )FH,! ED F:;I )FU, )>4( QR 5

5)FH,)))

2(! 5 5(

5I$_R

VEEDF:;I)FU, (

F:_{!5 #5 J%5}

R* 4<O

2(% 1J&5M%# M4F/_R

X66

0 % 5 )T, ):!;,M%

:!/!;!E;/,#J ( (

&5M%# 5DQ :F/I_R

/"5"A5\"%6<A5O682NCNEQ

/"6)5$GCDNO0+Q" bCBGMO0$Q))DS

/"7A5 bCBGMO0$Q (,6<A5O6

: 04 051 D(

EN,G

05)T,(% ( 51 (

( ! 2( (5<=(! ( #<=(1R #5!=!(1&49 ( R ( # 0" ! ( 2( (5 #! 2( <O

(R E(<O ,M% )(<= 5

,((<=52( 45( = M% )>4(:.,F!F;_R

5)T, M%5 (

&5M%= 52( B5 ( ( ! 5 ( ( = %4 R

( 4B1 2(5)T,

=5(FI_R!2(

5! 5 )T, #

5 ( ( R!!% # 5 5<= ( 5R> 2((<=(

<O &5M%5 <5)T,!

5!( 4<O ( 5 0" ! (42()T,(50" FI_R

0(!5)T, # #

4 ( 2( ! 5!#5(! 4#!5

5 :!F;_R

0,.%(;%(((% &,("+0..,1*+(

+1 ( 4 ( 9

FF$;_{( ,M% 2(2( !}

5 5 0G; ):!; )s/),

M%,t,I!%!:.,)FT,R05M

<=(!0G; )FT,0G;)FJ,)>4(::,! 2(#50" 5 **R

0<=0G;)FJ,0" #5 ( ((

5!# !55 B 0" R 5% 5 <O

1 4<O &49 4(5 # # % F;!$I!$F_R

0<=0G; )FT,5Z((

#1 ( # ( 5 $$_R

0(!0G; )FT, 1 ( 4F/_R

( 4 ( 2(=5 % 1 R:F!"C T < M 5B 1 5 4 M%

5( &5M%:_R05=!1

1 ! )FM,)FK,!9 %

( 5M#1 :!/.!$;_R

0<= /M)FM,5

( #4<= # 5 (<=

V!4(5!)

#9(;_{R 55 1}

4 J & #4<= ( & / I$_)>4(:/,R

05M # (<=! )FM, ! =!

)FL,! M% 5 (

( )>4(:,R

)FK,! (<= 4(5 ) ,1 5 <=5 49R( &5M%! 4(5 ( &% Z( ) ,!( V

1! 23<= 4:_R

/"0%"666)A5)6"

O1QGS

/"0$"A5)UE

/"00!?9" KD,O01Q6A5

( ( )FK, ( 2((<=%( 4(5

<=J ! (;&%

)FG, Z( )HI,R -! M # 15

<=(!42(%)HF,2(

5 ((#J)FG,)HI,)>4(:;,:_R

0#<=)HF, ((!=!(5&(

<= )FK, ( R! 5

5 (2(0'

5(#(( !5(

4(5)FK,!5 <= !

&%!_{R0 (<= 4(5 J <=}

#<=)HF,R05=!

)FK, (( 0"-)X0C

"C-(4&5CY,_{R 5#(}

<= 1 ( 5M#1 ( ( B(4 5)0, 5#54 5

( ( .!:_{R ! (}

( !R& 4 !5M <=

(<=54 !04 J ( ( !

4(! )FK,)5M#1,._{R !}

=!(5( 55!

(#)>4(:I,!4=(_R

0 1 ! (

( 9 ._!!5%5!

5% #1 .!/!_{R <=}

49 )***,5 R0

4 <= 5% )***,)#4(<=F_!

% 5,#2( 5% B ! 5! <O &M 23 4 =% R0(<= V 5% )***, 4O &5M% ( M 5 #2(5 (<=)***,)**, 1#%5 ( R5%)**, ( ## <O ( (<=514(! 4 s)7_/,_Ft/p_)>4(:F,.!/!_R

/"0+"A5)""A5"O04QO682UEUDQ

/"04$A5"6'O111QME

/" 02 6A5 ?"% 6 (!0& ;

!" ,ESUGEO05QO68MCQ

04 051 D(

EN,G

+1 5% 5# !

!2(5 (& )

#5%)HH,.!/!_R

0&(+.%'2(7+&%+(

<=( 5<= #1 #(( #1 M% R15(# 5B 5M#1 5 5( ( ! 2( M 5M

(<=))R0 % 9( <O

&5M% ( M 5 %5 5M#1 ( R05 1 %5 ( 2( 5 ( 5M # (<=! !!(15( (!5( 5 R0 2(B( 2( 55 V # 2( ( 5 #1 ( 8 2(5 ( M R

% .%+$&,0(

( %5 ( 4 J-#RR0R>R-!>(>1)>,!5( ( (4 O R

.7.E&+%(

:R U(4!DRR_"$%9!(U4LE

S!:;!5RI$R

/R ##! -R DR_ E(! ER TR! R_*" e *" $

"<&62!Q7LES!:F!5R

.;R

R UC! UR0R_&! DR0R_ E'Q!R_ !0RR_$"

0"FGLI!EM!:R

;R >C! TR R_ @'! R @R_ T ! "R 0R_06 8

"+!T YT'4 LD!:I!5R//;IR

IR S!ERUR_ 8 "FGGT!ETC!;/R

FR S!ERUR_#,1FGLG!UC!I$.R

$R +(5!-R_UQ '!>R_'(##!-R_FGLG!DM!F;;R

R !R_B!"RUR>R_@B!@R>RR7R_$"0"FGGL!

NS!:R

R DQ!SRR_!0RSR_FGGL!NU!:;.R

:.R 7!R_E 4!R0R_0608/+!

SRDR@55L-&5&!:R

::R T##! R R_$@ "+! S& TC Y L Q

P'!::!5R::;IR

:/R "C!TR0R_&/HIII!C!/IR

:R DQ!SRR_FGGG!NM!IFR

:;R &!DR0R_@!SRR_!0RR_FGLF!DC!$R

:IR @!0RSR_ C!@R0R_& 'C!RTR_!0RR_#"

FGKH!CN!:/;$R

:FR T(&!RR_&08"+!0 - L

@!:F!5RF$$:FR

:$R !ERDR_&/"+8((( !

0- L@!:/R

:R "C!TR0R_T !TRER_#"FGLM!EM!$R

:R @!0RSR_!0RR_$"0"FGKM!EN!/.FR

/.R -!DR"R_T !TRER_##!R_"C!TR0R_#"FGGH!

SN!/:;R

/:R E'Q!R_UC!UR0R_!0RR_1#/$

0+FGLH!U!$IR

//R UC!UR0R_E'Q!R_!0RR_FGLI!DB!/IFR

/R +4& !0RSR_(C !R_&!SRUR_FGKM!SG!$F:R

/;R !7RTR_ FGKK!CMT!I/$R

/IR b!R R_DQ!SRR_@!RSR_7 !+RUR_@!TRTR_1

#/$0+FGLM!CE!:/R

/FR D4!0R_$HIII!N!:IR

/$R T''! R_ (! 7R_ '! UR_ &(! R_ U! R_ U!

7R_U(!R_>(B!PR_ "FGJL!U!//R

/R !0RR_FGLL!DU!$$IR

/R D'!ER_&QC!"R_0!7R_U !R_7(4& !RR_!

0RR_E'Q!R_ !R_FGGU!NSI:/$R

.R EB '!RER_T !ERR_")FGGL!MU!/$/R

:R U &!R_(!UR_ '!UR_&(!R_'& &!R_ (!

R_#"FGKF!CD!:.R

/R 4#Q!"R0R_&(4!SRR_&)FGLK!CD!/:R

R *C4!DRR_E !TR0R_!SRSR_#"FGLG!SE!:FFR

;R 0! 7R_ U!PR_0 &Q! R_ ! R_ ! UR_ U! R_

U !R_#"FGGT!ST!:$;

IR "C!TR0R_T !TRER_!'6/61)(HIII!CE!/R

FR >C!7RR_&!DR*R_!R@R_ !-R*R_ 'C!SR_!

R-R_"6FGMK!NC!/R

$R 7##C!DRR_!PR7R_-5!ER_> &!"R_T !@R"R_E'Q!

R_!0RR_ '!R_> &!SRSR_1#/$

0+ 66"CFGGM!SG!:R

R !R0R_5'5!TR R_&FGLK!DS_/IIR

R '5T ! R! 7' ! 7R ER_ - ! R SR_* 0"

FGGM!ET!;/:R

;.R DC!RR_TC!R"R_> !>R_7C!SR0R_U%!ERSR_@Q !

0R"R_T'!-R_$#FGGK!TG!:IFR

;:R & !SR7RR_-4!0RRR_+0'!DR0RR_@ !TRSR_ " D"! R_+ D(4! R R @R_ U! *R_ U! ER R_

!R_+QB!SR_#,1FGGT!UG!.FR

;/R T !SR_- ! R_(!R_7('!TRTRR_U%!@R_T##!

*R_+QB!SR_!#FGGJ!SC!IFIR

;R E(&!0RR_!R_ !+R_1#/$0+FGGL!

DE!$IIR

;;R >('(C!R_!R_&FGLG!SB!F;:R

;IR -!RR_4( !RR_75' !-RDR_$"HIII!

U!:$R

;FR EB '!RER_T !ERR_$"HIII!U!::R

;$R 7(4!7R_EB '!RER_T !ERR_75' !-R_&

FGGT!SN!FFR

;R 0 !RR_$$FGKU!EM!;R

;R E(&!0RR_U(#!UR_$#FGKJ!DU!/.R

I.R C!PRR_E(&!0RR_FGKL!SU!/$;IR

I:R @!R0R_)"$?9"b) 50FGGL!SD!IR

I/R U%!ERSR_> !>R_S!R_E !SRSR_$"0"

FGLL!ST!;FF:R

IR U%! ER SR_ > ! >R_ &'! R_ E ! SR SR_$"

0"FGGF!DE!:F:R

I;R 0 !RR_FGGH!CSE!:/R

IIR 04Q!UR!R_D !URDR_&4!ERUR_#"FGKG!EE!IR

IFR '4(&! R_T! RTR_04Q! UR R_# "FGLH!EN!

:R

I$R 7C!R-R_T !TRER_ !SRTR_-!DR"R_"C!TR0R_

#"FGGT!ST!:R

IR 7C! R -R_ @! 7R 7R_T !TR ER_ E ! -R DR_ "C!TR0R_#

"FGGJ!SU!:/R

IR S' ! R R_ C! R0R_ X ! -R_ &4! R "R_ ! R_

#!*RSR_0 !RR_>!RR_(!RSR_!R0R_#

"FGGI!SS!/F.R

F.R C!R0R_&4RR"R_T!-R_#!*RSR_5& !R

0R_>!RR_#"FGGH!SN!I$R

F:R C! R0R_ &4! R "R_ &Q! 7R "R 7R_ #! *R SR_

5& !R0R_>!RR_0 !RR_((()+FGGU!

CB!/;R

F/R @!0RR_T !TRER_&' 660"HIII!CGS!I.R

FR DQ!SRR_$#FGGU!GT!::FR

F;R DQ!SRR_&+HIII!G!:I$R

FIR U !RR_7'4!"RSR_ !SRTR_!DRR_T( !DRR_

FFR T !TRER_0 !ER>R_"C!TR0R_#"FGLG!SE!/R

F$R T !TRER_&5 !@R7R_0 !ER>R_"C!TR0R_#

"FGLG!SE!:R

FR "C!TR0R_0Q!RSR_0 !ER>R_T !TRER_#"

FGGI!SS!:/R

FR (&C!ERR_55!SRSR_&!SR-R_S Q4!R_D&!ER>R_#

"FGGT!ST!:F:.R

$.R !R_T !TRER_"CRTR0R_#"FGGJ!SU!:/;$R

$:R 7C! R -R_ @! 7R 7R_T !TR ER_ E ! -R DR_ "C!TR0R_#

"FGGJ!SU!:/R

$/R @!7R7R_T !TRER_>C!"RR_bB!-R+R_-(!RR_"C!

TR0R_#"FGGM!SM!/I.R

$R !DR R_0Q!RSR_0 !ER>R_T!-R_ -(!R R_

T !TRER_"C!TR0R_#"FGGK!DB!::R

$;R !DRR_7' !URR_-(!RR_bB!-R@R_"C!TR0R_T !

TRER_$"0"HIII!GB!FR

$IR UQ! R ER_ 7B! R +R_ C! *R 0R_ ! SR SR 0R_

- !@R7R_$#FGGJ!TE!$FR

$FR - !@R7R_'Q!RER_$#HIII!US!:IR

$$R 7B!R+R_UQ!RER_>C!R-R_C!*R0R_-

@R7R_7 !"RR_$#FGGM!TS!;R

$R -!DR"R_T !TRER_-(!RR_"C!TR0R_#"

FGGI!SS!::/R

$R 0Q!RSR_C' !DRR_X!RSR_"C!TR0R_#"

FGGT!ST!$:R

.R -!DR"R_T !TRER_0Q!RSR_&(!"R_K(!KRbR_"C!

TR0R_#"FGGT!ST!/:$IR

:R -!DR"R_bB!-R_"C!TR0R_T !TRER_#"FGGJ!

SU!://R

/R !R_T !TRER_0 !ER>R_"C!TR0R_#"

FGGM!SM!:.;R

R @! 7R 7R_ -! DR "R_ T ! TR ER_ "C! TR0R_$

"FGGL!U!:$;:R

;R T !TRER_>C!"RR_!R_0 !ER>R_"C!TR0R_

FGGL!CDM!/$R

IR !-R_D&!"R_# "" FGLI!CBE!;$R

FR DC !SR-R_D(!RR_ &!RDR_D&!"R_ !-R_# ""

FGLU!CBN!/.R

$R !ERUR_D'!R"R_ !-R_# "" FGLT!CBG!:;.R

R 0'!RR_!ERR_&Q!ER>R_ !DR_> !>R_

U%!ERSR_$"0"FGGH!DD!//R

R 0'!RR_!ERR_&Q!ER>R_T !TRER_"C!

TR0R_ -! DR "R_ U%! ER SR_ > ! >R_ T !0R_$"

0"FGGJ!NB!F.R

.R D4 &Q!UR"R_&!RUR_54!RSR_E4 !RR_ /

FGGT!N!$R

:R &!RR_>!R*R_K",)FGGG!EE!$IR

/R T!"RR_-!DR"R_T !TRER_"C!TR0R_#"

FGGU!SG!:R

R T!"RR_-!7RER_-(B!>RDR_0 !ER>R_D& !-RSR_