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On the DNA Recognition Role of the Carbohydrate Sector in Calicheamicin A Comparison of DNA Cleaving Capacity of Enantiomeric Calicheamicinones.

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would be helpful in planning extensions of these findings.
Studies addressed to such issues as well as to proposals
relating to the mode of action of mamanuthaquinone are in
progress.
E.uprrinirritcil Procedure
ence map and included to set the orientation of the other two hydrogen atoms.
Further details of the crystal structure investigation are available on request
From The Director of the Cambridge Crystallographic Centre. 12 Union Roiid.
Cambridge CB2 1EZ (UK) on quoting the full jounal citation
1191 While we were unable to obtain a sample of the natural product. our assignment is secure given the crystallographically verified structure of 8 and the
complete correspondence of the high-field ' H and " C NMR spectra ofsynthetic 1 with those reported.
8: To :in ice-cold solution containing 7 (208 mg. 0.74 mmol) and T H F (0.06 mL.
1 equiv) iiiCH,CI, (5 mL) was added 1.8 M EtAICI, in toluene (0.60 mL. 1.5 equivj.
followed hy clow dropwise addition of 3 (0.20 g. 2 equiv) in CH,CI, (2 m L ) . After
the addition was complete. the mixture was allowed to warm to room temperature
and stirred for 6 h The reaction was quenched by cautious addition of saturated
NH,CI iit 0 C. l'heaqueous layerthat separated wasextracted with CH,CI, and the
combined organic phases were dried (Na,SO,), concentrated in w c u o , and chroinatograpiied on silica (l0:l to 4:l 1ienane:'EtOAc) to give 263 mg of 8 as a white
solid (X4"b). n i p . 122-124'C (CH2CIZ,'hexane);IR (CDCI,): Fmds= 2939. 1680,
1484.1465.1424.1257.1225.11Y7cm~i:'HNMR(300MHz.CDCI,):b=6.55(s,
1 H. phenyl). 5.43 (d, .I = 4.3 Hz. 1 H. vinyl). 3.87 (s. 6 H). 3.73 (s. 3 H).3.70 (s.
3H).~.~O~d..l=l2..iHz.lH).2.25(m.lH).2.0~1.7(m,3H).1.2-1.0(m.3Hj,
1 . 0 7 ( s . 3 H ) .1.~12(~.3H).0.92(d,J=6.9H11j.O.XY(s.3H):'~CN~4R(75MHz.
Jayshree Aiyar, Stephen A.
3.2. 149.2. 148.X. 145.7. 138.9, 138.5. 132.8, 115.6. 99.6. 62.0. 61.5,
Kevin K. C. Liu, Samuel J.
41 2. 36.5. 33 9. 31.2. 30.3. 29.8. 28.0. 32.7. 17.1. 12.0: MS (20eV
Donald M. Crothers
E I ) . i i i I (I-el.i n t . ) : 416 ( 1 ) [M']. 280 (1). 225 (100) [aroyl+], 210 (6). 191 (4);
high-re\oliitioii FAB MS for C,,H,,O,. calcd 416.2564, found 416.2540: correct
elemental aiialysis.
The antitumor activity of
On the DNA Recognition Role of the
Carbohydrate Sector in Calicheamicin:
A Comparison of DNA Cleaving Capacity of
Enantiomeric Calicheamicinones**
Received: November 26. 1993 [Z6516IE]
German version: A i g e w . Chciii. 1994, 106. 923
[ l ] For a series of reviews on marine natural products including those from
sponges. \ee: D. J. Faulkner. Nu/. Prod. R~p.por/.s1992, Y. 323 and i t s forerunners.
'I) M Kondracki, M. Guyot, Tetrriherlruri 1989,45. 1995: b) M. Kondracki. M.
C;u>ot. 7?iruhedroii Lrti. 1987. 5815: c) J. Rodriguez. E. Quinoa. R. Riguera,
B M Petei-s. L. M . Abrell. P. Crews. Z,rriihrriron 1992, 48. 6667.
131 B. W. Sullibaii. D. J. Faulkner. G . K. Matsumoto. H. Cun-heng, J. Clardy. J
Oix. C'ii<wi. 1986. 51. 4568.
[4] n) P. S. Sai-in. D. Sun. A. Thornton, W. E. G. Miiller. JNCI. .l
Nu//. Cuncer
/ m / . 1987. 78. 633: h) S . Loya, A. Hiri. FEES Let,. 1990. 269, 131.
[ 5 ] J. C. Swerse), L. R. Bgirrows. C. M. Ireland, Tetruhrdron Let/. 1991. 6687.
[6]Sec tbotnote 3 of ref. [Zc].
[7] K Alder. G . Stein. A i i j i r i i . . Chem. 1937, 50. 510.
[XI " I i i i ~ ~ r i i i o l ~ ~ ~Diu1.si r l t , , . A k l w Rcuciion~":W. Oppolzer in in Ciiiiipre/i~,n.si~,~,
Or, q [ i i i i < ' .Siw/h.\i\. b?~/. 5 (Ed.: B. M. Trost): Pergamon. London. 1991. Chapt.
4.1
[9] R B Woodwiird. T. J Katz. rcrruhrt/ron 1959. 5. 70.
[lo] .I (i. Martin. R. K. Hill. Chriii. Rc>r. 1961, 61. 537.
[l I ] :ii L: Kobuke. T F.ueno. J. Fiirukawa. J A m . Chtwi. So1 1970, 97. 6548: for
more recent examples employing Lewis acid catalysts. see b j F. Ribiere, 0.
Ri:int. H. B. K a p n . f i , m i / i ~ v / r mA . ~ ~ m ? i i w t i1990,
:i~
1, 199, c j K. Furuta, S.
Shiinizu. Y. Miwa. H. Ydmamolo. J Org. C/iei?i.1989.54. 1483; d j H. Takemu-
[2]
N. Komeshinxi. I Takahashi, S. Hashimoto. N. Ikota. K. Tomioka. K.
Kogi. E3frulirdronLer/. 1987, 5687; ej M. Reetz, S. Kyung. C. Bolm, T. Zierke,
Ciiciii Itid. Loridoii 1986. 834.
[ I ? ] The concept of a specific oid(i-orienting preference of methyl groups by a
(5 interaction lids been suggested [l la]. However. the explanation given in the
text. M hich is based on steric interactions. seems more likely in the light of the
f i i c t that ii similar E.w preference is exhibited by z-haloacrylic acids (see [lo]).
Alw. quite recently. Lewis acid controlled variation ofent/o:c.w selectivity in
ii irtero-Diels-Alder reaction has been reported: L. F. Tietze. C. Schneider.
S i i i l i ~ i i1992. 755.
1131 K Mikaini, M. Tei-ada. Y Motoyama, T. Nakai. 7 i ~ i r d i ~ d r oAws y m i w i r v 1991.
647.
1141 E. J. Core). M . C . Desai. Tefruheiiron LPII.1985, 5747.
[15] F. Beiiingtoii. R. D . Morin, L. C Clark, Jr., J. Org. C k m . 1955. XJ- 102.
1161 S. N d i m . S. M. Weinreb, Tetrul~erlronL e i / 1981. 3815.
1171 S. P. Tani\. Y. M. Abdallah, Si.n/h. Coininun. 1986, 251.
[lX] X-ray crystal structure analysis of compound 8: C,,H,,O,, triclinlc, space
g r o u p d ( n o . ? ) . o =9.9014(6).h =10.322(1),c =12.188(1)A,a = 85.161(7).
/{ = 69.095i6). 7 = 87.714(7) . I; =1159.4(4) A'. Z = 2.
= 1.193 gem-'.
/!(MokJ = 0.8 cm-! Of the 4548 reflections collected, 4294 were unique and
2526 reflections uith I > 3 n ( I ) were used in the refinement of the structure;
R = 0 045. R \ 4 = 0.055 The residual electron density was less than 0.15 e k J .
Eiiral'-Nonius CAD4 diffractoineter. Mo,, irradiation, 2H,,,, = 50 , sturctiire
deterinination by direct methods (MITHRIL). all hydrogen atoms were included in calctdnted positions. cxcept those belonging to methyl groups in
which case one hydrogcn atom of the methyl group w a s located in the differ-
Hitchcock, Derek Denhart,
Danishefsky,* and
the naturally occurring drug
calicheamicin 7: (1) is believed to operate through its efficient
cleavage of duplex DNA in a double-stranded, highly sequenceselective fashion.['%*] The drug i s comprised of an aryl tetrasaccharide carbohydrate region tethered to an enediyne-containing
aglycone moiety. The latter, which is termed calicheamicinone.
was synthesized first in our laboratory as its racernater3' (2/3)
and subsequently in the enantiomerically pure form corresponding to the natural product, by Nicolaou et al.[41
SSSMc
1
'+Mon
rii.
OH
Calicheamicin yi reacts with supercoiled phage D N A to produce a ratio of double- to single-stranded cuts of 1:2.''' The
[*I
Prof. S.J. Danishefsky!" Dr. J. Aiyar. Dr. S . A. Hitchcock. Dr. D Denhart,
Dr. K. K. C . Liu. Prof. D. M. Crothers
Department of Chemistry, Yde University
New Haven. CT 0651 1 (USA)
Telefax: Int. code + (203)432-5098
[ '1 New addresses: Memorial Sloan-Kettering Cancer Center
1275 York Avenue, New York. NY 10021 (USA)
Telefax: 1nt.code + (212)772-8691
and
Department of Chemistry. Havemeyer Hall
Columbia University. New York, N Y 10027 (USA)
Telefax: Int. code + (212)854-7142
[**I
This rescarch was supported by the National Iiistitutes of Health (Grants No.
CA 28824 and GM-21966) A NATOjSERC (Science and Engineering Research Council (UK)) Fellowship to S A. H.. a National Research Council
(Canada) Predoctoral Fellowship to D D.
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propensity for this enediyne drug to exact double-stranded cuts
is more pronounced than that of many other D N A cleaving
agents.16] In contrast, racemic calicheamicinone (2/3), which
lacks the carbohydrate sector, exhibits sharply reduced capacity
to effect such double-stranded cleavage[’] and furthermore exhibits none of the sequence selectivity displayed by the intact
drug itself. Nonetheless, quantifiable genuine double-stranded
cutting events are detected with the aglycone racemate (the ratio
of double-stranded to single-stranded cuts is about 1 : 30) .[’I In
addition, reaction of D N A with racemic calicheamicinone, under conditions where the enediyne sector suffers reductive cyclization, leads to only 10 % hydrogen incorporation into the
aglycone by direct transfer from DNA.[’] This is in contrast to
the situation in 1, where 80-90% hydrogen incorporation by
transfer from deoxyribose residues is observed in the course of
reductive aromatization.[’]
R
OH
Meo2c&
HO
OH
HO
2 R=SSSMe
4 R=AcS
thesis and converted to the two antipodes of calicheamicinone (2
and 3) .[lo,
The kinetics of supercoiled phage D N A cleavage were monitored in experiments in which S-acetate enantiomers of natural
(5) and unnatural absolute configuration (4) were incubated
with DNA. Figure 1 shows that the two enantiomers displayed
different degrees of double-stranded cleavage. Surprisingly, the
unnatural enantiomer, 4. with a double- to single-stranded cutting ratio of about 1 :20 is four to five times more efficient in this
sense than is the natural enantiomer (ratio of about 1 :90 at the
same concentration). On the other hand, the overall cleavage
rate, the sum of single- and double- stranded cutting rates, does
not differ detectably for the two enantiomers.
The absolute amount of double-stranded cutting measured in
these experiments using the S-acetates 4 and 5, though still
formidable relative to conventional reagents, is small compared
with calicheamicin itself. Therefore we do not presently propose
a detailed model to explain the significant and reproducible
difference in the double-stranded cleaving capacities of the two
enantiomers. A possible direction for interpretation of the trend
could be the presence of hydrophobic pockets in the minor
groove which favor the free unnatural S-acetate 4 over its natural
counterpart 5 in certain conformations. which allow for doublestranded
We note that the possibility of enantioselective bias in the interaction of ligands with oligonucleotide
hosts has been addressed in the elegant investigations of Barton
et al.[l3l and more recently by Boger et aI.[l4]However, this is
the first such finding in the enediyne drug area.
3 R=SSSMe
5 R=AcS
0.02
-
0.015
Preincubation of linear duplex D N A with the carbohydrate
domain of calicheamicin in the form of its methyl glycoside 6,[81
followed by incubation with racemic calicheamicinone led to
modulation[9d1of the virtually uniform cleavage pattern observed
in the absence of the carbohydrate.”] A similar capacity is exhibited by the racemic S-acetate (4/5), a precursor of calicheamicinone. However, in contrast to calicheamicinone, which relies
on a trisulfide trigger, the racemic S-acetate 4/5 has the advantage of being readily activated for diyl formation at pH 8 without recourse to exogenous reducing agents.’’]
t
0.005 -
-0
0.05
0.04
1
The experiments described herein assess the contributions of
each of the aglycone S-acetate enantiomers (4 and 5) to the
double-stranded cutting and sequence selectivity observed in
our previous studies with the ra~emate.~’]
Compounds 4 and 5
have been prepared in enantiomerically pure form by total synP-:
VCH Verlagsgeselbchu/r mhH, D-69451 Wrinheim, 1994
-
1
1.5
1/21
0.2
0.4
0.6
-
0.8
f
N1
Fig. 1. Agarose gels illustrating the different degrees of double-stranded cleavage
displayed by the enantiomeric aglycones 4 (bottom) and 5 (top). Supercoiled
~
was incubated with 0.2mM 4 or 5 in
@X174(RFI) DNA ( 4 0 in~ nucleotides)
50mM tris(hydroxymethy1)aminomethane (Tris), pH 8.0 at room temperature. At
various times, 3 pL aliquots of each reaction mixture were added to 3 pL loading
dye (0.02% bromophenol blue in 8 0 % glycerol) and resolved on a 1 % agarose gel
in 1X TAE buffer ( 4 0 m ~Tris a c e t a t e i 2 m ~EDTA) run at 6-8 V c m - I . The gels
were stained in a 1.3 pgmL- ethidium bromide solution and photographed with
Polaroid 66s film. Negativcs were scanned by using a model 1650 scanning densitometer (Hoefer). The average number of single-stranded (NI) and double-stranded
(N2) cuts per molecule were calculated as discussed earlier [S]. assuming a Poisson
distribution for the formation of Form I1 (nicked circular) and Form 111 (linear)
cleaved products from Form I (supercoiled) DNA. The data from the first 5-7 min
of the reactions can be fitted to a linear equation (top and bottom right, respectively), giving the ratio of the average number of double- to single-stranded cuts per
molecule. For both gels. lane 1 . untreated DNA, lanes 2-9: extent of the reaction
at 1. 2, 3. 5, 7 . 10. 15, and 20 min. respectively.
‘
OH
856
N1
I/
0
H o M a 02 g /
0.5
0
0.01
6
;
0.01
N2
0570-0R33194;080X-0856$ 10.00+ .2S/U
Angew. Chem. I n f . Ed. Engl. 1994, 33, N o . 8
1.2
COMMUNICATIONS
When the D N A was preincubated with the methyl glycoside
of the aryl tetrasaccharide domain of calicheamicin y: 6 ( 5 p ~ ) ,
prior to addition of the aglycone, it was found that the doubleto single-stranded cutting ratios decreased in both 4 and 5 (to ca.
1 : 50 and 1 :200 respectively, Fig. 2 ) . Possibly the carbohydrate
preferentially binds the phage D N A at sites which would otherwise be targeted for double-stranded cutting by the aglycone.[’’]
However, the unnatura1 S-acetate enantiomer 4, retained its
greater efficacy as a double-stranded cleaving agent relative to
the natural antipode 5 even under these conditions.
0.006 1
/
o.oo2:
0.001
-
0
0
0.2
-
0.4 0.6 0.8
N1
1
1.2
Fig. 3. Sequence selectivity of the aglycones in the presence ofargl tetrasaccharide
6 bound to DNA. The D N A sequence [5,9a] was designed to include several
cdlicheamicin cleavage sites. Oligosaccharide and [3’-’’P] bottom-strand labeled
DNA duplex (“bottom” with respect to orientation of calicheamicin ?/: at the
recognition sites) were preincubated in lOmM Tris’HCI (pH 8.0). 1 mM EDTA, 2 %
T H F for 1 5 rnin at 25 C . Aglycones 4. 5. or a racemic mixture of 4 and 5 (3.2mM)
were added to the reactions. and incubation continued for 2 h. The DNA in each
reaction was ethanol-precipitated, resolved by electrophoresis on a 1 0 % denaturing
polyacrylamide gel, and autoradiographed. Lanes 1-4. reaction with racemic mixture of 4 and 5 : lanc 1 , DNA + aglycone: lane 2. DNA preincubated wirh 20 p v
oligosaccharide aglycone; lane 3 , raine as lane 2. but with 0 1 mM oligosaccharide: lane 4, same as lane 2. but with 0.5miv oligosaccharide; lane 5. DNA
5 pv 1 (dithiothreitol) DTT, reacted at room temperature for 5 min; lane 6,
A + G marker ladder. Lanes 9-12 and 14 18, reactions with individual ennntiomers 5 and 4. respectively: lane 7. untreated DNA; lane 8, A G marker ladder;
I
oligosaccharide + 5 ;
lane 9. DNA 5 ; lane 10, DNA preincubated with 20 M
lane 1 1 . same as lane 10, but with 0.1 mM oligosaccharide: lane 12. bame as lane 10.
but with 0 . 5 m ~
oligosaccharide; lane 13. DNA + 5 p~ I + DTT. reacted at room
temperature for 15 mm; lane 14, DNA + 4; lane 15, DNA prelncuhated with 20 p~
ohgosaccharide 4; lane 16, same as lane 15. but with 0.1 mhf oligosaccharide:
lane 17, same as lane 15, but with 0.SmM oligosaccharide: kine 1 % A + G marker
ladder. Brackets indicate strong cakheamicin 1,: recognition sites within the DNA
sequence used in these experiments. Arrows point to slrong aglyconemediated cleavage sites adjacent t o protected I-egions. in the presence of the
oligosaccharide.
+
0.035i
+
+
+
+
t
N2
+
0
-
1
0.5
N1
1.5
Fig.2. Chiral preference of the aglycones 4 (bottom) and 5 (top) in the presence of
the sacchai-ide 6 in the double-stranded cleavage of DNA (agarose gel chromatographs, left). Reactions were carried out as described in Figure 1, except that the
DNA w’as preincubated with 5 phf 6 for 3 5 min prior t o addition of 4 or 5 . Data were
analyzed as described in Figure I . and are represented quantitatively in the top and
bottom right panels. For both gels, lane 1 : untreated D N A 6 , lanes 2-9: extent
of the rextion at 1.4. 7. 10, 15.20,25, and 30 min. respectively. The ratio of double
to single-stranded cuts is equal to the slope of the line. and is accurate to about
i 1 5 “C
+
Thus, the carbohydrate domain, when bound to DNA, does
not appear to modulate the relative binding characteristics of
the two S-acetate aglycone enantiomers. In addition, preincubation of the linear duplex D N A used in earlier studies[’.
with
methyl glycoside 6 prior to addition of either 4 or 5 gave rise to
the same enhanced cutting sites flanking the carbohydrate-protected regions as were found with the racemate (Fig. 3). As
before, the most prominent of the enhanced sites is at the underlined G in the C G G A sequence (marked by the lower bracket on
the right side of Fig. 3). This sequence serves as one of the
calicheamicin recognition domains included in the design of the
D N A fragment.[51Quantitative analysis of the gel chromatographic data (not shown) gives enhancement patterns for the two
enantiomers (lanes 9- 12, 14- 18) which are indistinguishable
from the results we reported earlierrga1for the racemic mixture
(lanes 1-4). Note that the enhanced sites (marked by arrows)
are adjacent to, but frequently d o not correspond exactly to
calicheamicin y’, cleavage sites, which can best be seen in lane 13.
In summary, it is clear that the carbohydrate sector provides
the bulk of the D N A recognition of the drug. Yet, in the absence
of a covalent link between the recognition and effector (enediyne)
domains, the carbohydrate is unable to override or measurably
modify the inherent differences of the antipodal S-acetate: D N A
interactions. It would therefore be of great interest to determine
whether the carbohydrate domain when covalently joined to
each of the enantiomeric aglycone antipodes, could modulate
the characteristics of the drugs through their enediyne sectors.
Clearly the covalent attachment of the ent effector to the
natural recognition domains can only be accomplished through
the medium of organic synthesis. Another fascinating synthetic
goal is that of creating hybrid agents where the effector domains
of established clinically useful drugs are joined to the powerful
carbohydrate recognition domain of calicheamicin.[‘’I On the
basis of ongoing experiments. we have reason to believe that
such goals are not unrealistic.
Received: January 8. 1994 [Zh5341E]
German version: Angcu. C‘hrm 1994. 106. 925
[ I ] a) For a critical revie%’of the field of endiyiie antibiotics see: K. c‘. Nicolaou,
W.-M. Dai. Angiw. C/ziv?z.1991. 103, 1453; Angew. C h i m h!. Ed. Engi. 1991,
30,1387; b) For the total synthesis ofcalicheamicin see: K . C Nicolaou. C. W.
Hummel, M. Nakada, K . Shibayama, E. N . Pitsinos, H Saimoto. Y Mizuno,
K.-U. Baldenins, A. L. Smith. J. A m . Climi. Sor. 1993, /IF. 7625. and references therein.
COMMUNICATIONS
a ) M. D. Lee. T. S. Dunne, C. C. Chang, M. M. Siegel, G. 0. Morton, G. A.
Ellestad. W. J. McGahren. D. B. Borders, 1 Am. Chem. Sot. 1992.114.985: b)
M. D. Lee. G. A. Ellestad. D. B Borders, Aec. Ch<>m.Res. 1991,24.235:c) M.
D. Lee, T. S. Dunne. M. M. Siegel, C. C. Chang. G . 0. Morton, D. B. Borders,
J Am. Chcm Soc. 1987, 109, 3464: d) M. D. Lee, T. S. Dunne, C. C. Chang.
G. A. Ellestad, M. M. Siegel, G. 0. Morton, W. J. McGahren, D. B. Borders.
;hid.1987. I O Y , 3466: e) J. Golik, J. Clardy, G. Dubay, G . Groenewold, G. H.
Kawaguchi. M. Konishi. M. B. Krishuan, H. Ohkuma, K:I. Saitoh, T. W.
Doyle, ihid. 1987, 109. 3461; f) J. Golik. G. Dubay, G Groenewold, H.
Kawaguchi, M. Konishi, B. Krishnan, H. Ohkuma, K.-I. Saitoh, T. W. Doyle.
;hid. 1987, 109. 3462; f) N. Zein, A. M. Sinha, W. J. McGahren, G . A. Ellestad.
Scirncc 1988.240. 11 98: g) N. Zein, M. Poncin. R. Nilakantan, G. A. Ellestad.
rhid. 1989. 244. 697.
a) M. P. Cabal. R. S Coleman. S. J. Danishefsky. J. Am Chrn?.Sw. 1990, 112.
3253. b) J. N Haseltine. M. P. Cabal. N. B. Mantlo. N Iwasawa. D. S.
Yamashita. R . S. Coleman. S. J. Danishefsky. ihid. 1991, 1 / 3 , 3850.
a) A. L. Smith. C.-K. Hwang, E. N Pitsinos, G. R. Scarlato. K. C. Nicolaou,
J. A m C'hem. So<. 1992, 114. 3134; b) A. L. Smith. E. N. Pitsinos. C:K.
Hwang. Y. Mimno, H. Saimoto, G . R. Scarlato, T. Suzuki. K. C. Nicolaou,
ihid. 1993. 115. 7612.
J. Dr;ik. N . Iwaaawa. S. J. Danishefsky, D. M. Crothers, P r o ( . ~Vuri.Aiurl. Sci.
1 S A 1991. 88. 7464.
a) L. F. Povirk. W. Wubker. W. Johnlein, F. Hutchinson, N u l e i < Acid> Res.
1977.4, 3573. b) P. C Dedon. I . H. Goldberg. J. Bid. Chm7 1990. 265, 14713.
a) N. Zein, W J McGahren, G. 0. Morton. J. Ashcroft. G. A. Ellestad. J Am.
Chcm Soc. 1989, 111, 6888: h) C. A. Townsend, J. J. De voss, W.-D. Ding. G.
0. Morton. G. A. Ellestad. N . Zein, A. B. Tabor. S. L. Schreiber. ihirl. 1990,
112. 9669.
For syntheses of the carbohydrate sector see: a) R. D. Groneberg. T. Miyazaki.
N . A. Stylianides, T. J. Schulze. W. Stahl. E. P Schreiner. T. Suzuki, Y
Iwabuchi. A L Smith, K . C. Nicolaou, J Am. Chen7. Soc. 1993, 115 7593, b)
K . C. Nicolaou. R. I). Groneberg. T. Miyazaki. N . A. Stylianides. T. J. Schulze.
W Stahl. i h i d . 1990. 112. 8193: c) R. L. Halcomb, S. H. Boyer, S. J. Danishefsky. A ~ i j i r i i ('hon. Inr. Ed. Eng. 1992. 31. 338.
For DNA binding studies see: a) J. Aiyer, S. J. Danichefsky. D. M. C'rothers.
J. ,4111. Cheni.Sw. 1992. 114, 7552: h) K C. Nicolaou. S.X. Tsay. T. Suzuki.
G. E Joyce, ihid 1992. 114. 7555.
For the synthesis of enantiomerically pure intermediates toward oalicheamicinone see: V. P. Rocco. S. J. Danishefsky, Tetruhc~froriLcm 1991. 32, 6671.
The enantiomerically pure ketones 7 and 8 were obtained as previously described [lo] by resolution o f a racemic precursor. The ketones 7 and 8 were then
employed to access the enf and natural S-acetate congeners 4 and 5. respectively, by the method disclosed for the corresponding racemate [3]. The original
surmise [lo] concerning the absolute configurations of 7 and 8 has now been
reverqed.
A Convergent Total Synthesis of
Calicheamicin 7; **
Stephen A. Hitchcock, Serge H. Boyer,
M a r g a r e t Y. Chu-Moyer, Steven H . Olson, and
Samuel J. Danishefsky"
We have been concerned with the total synthesis of the enediyne antibiotic calicheamicin y', (l).",*I In 1988 we described the
first construction of a functionalized core structure corresponding to the aglycone sector of the drug. This synthesis showed the
feasibility of assembling such structures by a cyclization of the
type a + b, and the stereochemical ramifications of such a process at the emerging secondary alcohol.r31Subsequently, related
cyclizations have found application in a variety of other programs in the enediyne area.'41 Exploiting these findings, we accomplished the synthesis of descarbamoylcalicheamicinone (2)Is]
and, finally, calIcheamicinone (3)I6Iboth in racemic form. It was
shown that these systems. lacking the carbohydrate domains,
SSSMe
.r+o
1
Me0
OH
a
b
SR
7
8
[12] For a detailed proposed binding model for calicheamicin with DNA see. R. C.
Hawley, 1.L Kiessling, S. L. Schreiber, Proc. .Vat/. Acud. Sci. USA 1989, X6.
1105.
[13] a) M. D. Purugganan, C. V. Kumar. N. J. Turro. J. K. Barton. Scrmcr 1988.
241. 1645. b) H. Y Mei, J. K. Barton, Proc. Narl. Acud Sci. USA 1988, 85.
1339: c) J. K Barton. J. M Goldberg. C. V. Kumar. N . J. Turro, J Am. Chem.
Soc. 1986. IOR, 2081: d) J. K . Barton, E. Lolis, ;bid 1985. 107, 708: e) J. K.
Barton. J. J. Dannenberg. A. L. Rapheal, ihrd. 1982, 104, 4967.
[I41 D. L. Boger. K . Machiya. D L. Hertmg, P. A. Kitos. D . Holmes. J. Am. Chem.
Svc. 1993. 1I S . 9025. See also D. L. Boger. D. S. Johnson. W. Yun. C. M. Tarhy,
Broorji. Med. Chem. Leil. 1994, in press, D. L. Boger. D. S. Johnson. W. Yun.
J. A m . Chrin. Soi.. 1994. 116. in press.
[ I 51 For hybrids of synthetic DNA cleaving agents with the calicheamicin oligosaccharide region see. K. C. Nicolaou, E. P. Schreiner, Y. Iwabuchi, T. SuzukI,
Anjiew Chcm. 1992, 104, 317; Angeii'. Chem. h i . Ed Engl. 1992, 31, 340
2 X = H, R = SSMe
3 X = NHC02Me,R = SSMe
4X=H,R=Ac
5 X = NHC02Me, R = Ac
[*I Prof. S. J. Ddnishefsky.'" Dr. S A. Hitchcock, S. H. Boyer.
M. Y Chu-Moyer. S. H. Olson
Department of Chemistry. Yale University
New Haven, C T 0651 1 (USA)
Telefax: lilt code + (203)432-5098
[ '1 New addresses: Memorial Sloan-Kettering Cancer Center
1275 York Avenue, New York. NY 10021 (USA)
Telefax: Int. code (212)772-8691
and
Department of Chemistry, Havemeyer Hall
Columbla University. New York. NY 10027 (USA)
Telefax: Int. code + (212)854-7142
[**I This research was supported by National Institutes of Health (Grant No. CA
28824). A NATO 'SERC (Science and Engineering Research Council (UK))
Fellowship to S. A. H.. a Kent Fellowship to S. H . B. and M. Y. C -M.. and an
NSF Predoctoral Fellowhip to M. Y C:M. are gratefully acknowledged.
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sector, enantiomers, capacity, cleaving, dna, role, recognition, carbohydrate, calicheamicin, calicheamicinonen, comparison
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