Derivatives of methyl 5-methyl-4-oxo-1,2,4,5,8,8a-hexahydrocyclopropa[c]-pyrrolo[3,2-e] indole-7-carboxylate: A case of inverse electronic effects on the reactivity of CC-1065 derivatives

Full text of DOI:10.1021/ja005704n

5102
J. Am. Chem. Soc. 2001, 123, 5102-5103
by the notable and detailed work of D. Boger’s group, that the
introduction of electron-withdrawing groups causes a linear
decrease in speed of the acidic solvolysis. This, in turn, enhances
the stability of cyclopropaindolones in plasma and causes an
increase in in ViVo cytotoxic potency.3,4
Derivatives of Methyl 5-Methyl-4-oxo-1,2,4,5,8,8a-
hexahydrocyclopropa[c]-pyrrolo[3,2-e]indole-7-
carboxylate: A Case of Inverse Electronic Effects on
the Reactivity of CC-1065 Derivatives
These findings suggest that the best candidates for drug
development are those derivatives with greater electron-deficiency.
This study shows that this is not always the case, as 5-methyl-
CPI derivatives 2a-e were found to exhibit a nonlinear solvolytic
Luis Castedo,† Jose´ Delamano,† Juan Enjo,† Jesu´s Ferna´ndez,†
Dolores G. Gra´valos,§ Ramo´n Leis,‡ Carmen Lo´pez,†
Carlos F. Marcos,† Ana R´ıos,‡ and Gabriel Tojo*,†
Departamento de Qu´ımica Orga´nica y
Unidad Asociada al CSIC
UniVersidad de Santiago de Compostela
15706 Santiago de Compostela, Spain
Departamento de Qu´ımica F´ısica
UniVersidad de Santiago de Compostela
15706 Santiago de Compostela, Spain
PharmaMar, S. A., C/Calera 3
behavior, with a region of increased reactivity (log k) correlating
with decreased electron-deficiency as reflected by the σp Hammett
constant of their R substituents (Figure 1).
28760 Tres Cantos, Madrid, Spain
Compounds 2a-e were prepared according to Scheme 1. A
key reaction was the photochemical oxidative cyclization of bis-
pyrrylethene 6, previously developed by us.5 Condensation of
sulfone 46 with pyrrolecarbaldehyde 5, both easily obtained from
aldehyde 3,7 followed by oxidation with DDQ and acetylation,
leads to bis-pyrrylethene 6. This compound was obtained as a
single isomer about the central double bond, with an unknown,
but irrelevant, stereochemistry. The tosyl substituent in compound
6 stabilizes the structure against unwanted oxidation by singlet
oxygen and allows a very good yield in a photochemical oxidative
cyclization of such a densely functionalized compound, providing
pyrroloindole 7 in 90%. Protecting-group manipulations and
regioselective reductions of an indole and an ester, yield alcohol
12. Compound 8 was deacetylated to obtain a greater yield in
the regioselective reduction of the upper pyrrole ring. Cyclization
of phenolic alcohol 12 under Mitsunobu conditions, followed by
changing the substituents on the indoline nitrogen, leads to the
desired derivatives 2a-e, in which groups with different electron-
withdrawing properties are introduced.
ReceiVed October 17, 2000
The isolation of the antitumor agent CC-1065 (1)1 at the Upjohn
Company in 1978 marked the beginning of a series of discoveries
of natural and synthetic derivatives of cyclopropaindolones with
promising therapeutic properties.2 These agents retard cancer cell
growth by alkylation of the DNA in a highly selective manner.
The cyclopropane is attacked by the N-3 nitrogen of an adenine,
leading to the opening of the cyclopropane and the transformation
of the cyclohexadienone in an aromatic ring.3
The solvolysis of cyclopropapyrroloindolones 2a-e at pH 1.4
in a MeOH-H2O (1:1) solution was studied by following the
disappearance of the characteristic long-wavelength UV-absorp-
tion of the cyclohexadienone chromophore. All of the compounds
studied, with the exception of 2e, show a linear increase in
solvolysis speed with increasing electron-deficiency (Table 1 and
Figure 1). Thus, contrary to expectation, the simple unsubstituted
derivative 2a shows greater stability, while the N-acetylated,
electron-deficient compound 2d shows greater reactivity. Com-
pounds 2b and 2c show intermediate behavior. Surprisingly, no
solvolysis was detected after more than one week in the very
electron-deficient 2e. We estimate that it possesses a k of less
than 4 × 10-7 s-1, the corresponding point in Figure 1 displaying
this value. While the solvolytic behavior of sulfamide 2e is
abnormal in comparison with the structurally similar derivatives
2a-d, the decreased reactivity in a more electron-deficient
compound has ample literature precedent.3,4
An important aspect of the development of new cyclopropain-
dolone (CPI) derivatives with increased biological activity is the
possibility of predicting their potency by solvolytic studies. From
the study of many of these derivatives, it has been shown, mainly
† Departamento de Qu´ımica Orga´nica, Universidad de Santiago.
§ PharmaMar, S. A.
‡ Departamento de Qu´ımica F´ısica, Universidad de Santiago.
(1) Hanka, L. J.; Dietz, A.; Gerpheide, S. A.; Kuentzel, S. L.; Martin, D.
G. J. Antibiot. 1978, 31, 1211-1217. Chidester, C. G.; Krueger, W. C.; Mizsak,
S. A.; Duchamp, D. J.; Martin, D. G. J. Am. Chem. Soc. 1981, 103, 7629-
7635.
(2) Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Ogawa, T.;
Takahashi, K.; Sano, H.; Saitoh, Y. Chem. Pharm. Bull. 1995, 43, 378-391.
Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H. Bioorg. Med. Chem. 1996,
4, 1379. Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H. Bioorg. Med. Chem.
Lett. 1996, 6, 2147. Lukhtanov, E. A.; Kutyavin, I. V.; Reed, M. W.; Adams,
A. D.; Lucas, D. D.; Meyer, R. B., Jr. J. Am. Chem. Soc. 1997, 119, 6214.
Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem. ReV.
1997, 97, 787-828. Patel, V. F.; Andis, S. L.; Enkema, J. K.; Johnson, D.
A.; Kennedy, J. H.; Mohamadi, F.; Schultz, R. M.; Soose, D. J.; Spees, M.
M. J. Org. Chem. 1997, 62, 8868-8874. Muratake, H.; Okabe, K.; Takahashi,
M.; Tonegawa, M.; Natsume, M. Chem. Pharm. Bull. 1997, 45, 799-806.
Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett. 1997, 43, 7577-
7580. Atwell, G. J.; Tercel, M.; Boyd, M.; Wilson, W. R.; Denny, W. A. J.
Org. Chem. 1998, 63, 9414-9420. Boger, D. L.; Boyce, C. W. J. Org. Chem.
2000, 65, 4088-4100. Boger, D. L.; Santilla´n, A.; Searcey, M.; Brunette, S.
R.; Wolkenberg, S. E.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 4101-
4111.
Cyclopropaindolones 2a-e also show an abnormal relationship
between solvolytic reactivity and in vitro cytotoxic potency (Table
1, Figure 2) relative to other CC-1065 analogues,3 with those
compounds 2a-e with greater potency also having greater
(4) Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 116, 5523-5524. Boger,
D. L.; Han, N.; Tarby, C. M.; Boyce, C. W.; Cai, H.; Jin, Q.; Kitos, P. A. J.
Org. Chem. 1996, 61, 4894-4912.
(5) Antelo, B.; Castedo, L.; Delamano, J.; Go´mez, A.; Lo´pez, C.; Tojo, G.
J. Org. Chem. 1996, 61, 1188-1189.
(6) Castedo, L.; Delamano, J.; Lo´pez, C.; Lo´pez, M. B.; Tojo, G.
Heterocycles 1994, 38, 495-502.
(3) Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl. 1996, 35,
1438-1474.
(7) Anderson, H. J.; Loader, C. E.; Foster, A. Can. J. Chem. 1980, 58,
2527-2530.
10.1021/ja005704n CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 5103
Table 1. Solvolysis Ratesaand Cytotoxicity
agent (R)
2a (H)
2b (CONH2) 145 s
2c (Boc)
2d (Ac)
2e (Ms)
t1/2
kobs (s-1
)
IC50 (mg/mL)c
σp
g10 h
1.92 × 10-5
4.75 × 10-3
7.43 × 10-3
1.18 × 10-2
<4 × 10-7
2.5
0.05
0.5
0.02
2.5
0.00
0.31
0.45
0.49
0.72
93 s
58 s
very slowb
a Water-MeOH 1:1; [agent] ) 10-4; pH ) 1.4 ([ClO4H] ) 3.8 ×
10-2). b No solvolysis was detected after one week. c Values corre-
sponding to in Vitro cytotoxicity activity against P-338 cell lines. Similar
trends were observed in cell lines A549, HT29, and MEL28.
Figure 1.
Scheme 1a
Figure 2.
Figure 3.
behavior was also observed in the first studies on CC-1065
derivatives performed at Upjohn.8 The composite data from
previous works and our own show that there is an optimum of
solVolytic reactiVity, leading to a maximum cytotoxic potency, in
which cyclopropaindolone alkylators are not substantially de-
stroyed before reaching the DNA, but are still able to efficiently
alkylate DNA.
Quite curiously, as a result of a reversal of behavior for both
solvolytic reactivity versus electron-deficiency and solvolytic
reactivity versus biological activity, in the present series, with
the exception of 2e, a normal relationship of electron-deficiency
versus biological activity is found. The most electron-deficient
compounds are the most cytotoxic (Figure 3).
This work shows that to infer a linear relationship between a
physical constant and a biological activity; compounds with the
greatest possible range of the physical constant must be studied.
a (i) KOt-Bu, ClMOM, DMF, 88%. (ii) NaBH4, MeOH, 0 °C, 98%.
(iii) p-Me(C6H4)SO2Na, HCO2H, 95%. (iv) KOt-Bu, MeI, DMF, 95%.
(v) LDA, THF, -78 °C to -40 °C, 82%. (vi) DDQ, benzene, reflux;
ClAc, Et3N, CH2Cl2, -40 °C; 82%. (vii) hν, cat. I2, air, EtOH, 90%.
(viii) HCOOH, 98%. (ix) NaOMe, MeOH, 95%. (x) Et3SiH, F3CCO2H;
Ac2O, Py; 66%. (xi) Na, naphthalene, THF, -78 °C; Ac2O, Py; 50%.
(xii) LiAlH4, THF, -30 °C, 84%. (xiii) Ph3P, DEAD, THF, 71%. (xiv)
NaOMe, MeOH, 91%. (xv) HCl (g), EtOAc; Et3N, Me3SiNCO, THF;
Et3N/H2O/CH3CN (1/1/5); 26%. (xvi) Boc2O, DMAP, CH2Cl2, 99%. (xvii)
ClSO2Me, Et3N, CH2Cl2, -20 °C, 45%.
Acknowledgment. We thank the Spanish Ministry of Education and
Culture (PB97-0524), Xunta de Galicia (PGIDT 99PX120904B), and
PharmaMar, S. A. for financial support. J.D. thanks the Spanish Ministry
of Education and Culture for a predoctoral research grant. J.E. and C.L.
thank the Xunta de Galicia for predoctoral research grants.
solvolytic reactivity. This could be due to the general lack of
solvolytic reactivity of compounds 2a-e, as suggested by the
fact that it is necessary to carry out the kinetic studies at a very
acidic pH of 1.4. Thus, while normally the more stable com-
pounds, which remain intact until they reach DNA, show greater
cytotoxic potency, in the present series the reverse is true. This
can be explained if no degradation occurs in the present series in
competition with DNA alkylation, so greater activity is seen for
those compounds that react more efficiently with DNA. This
Supporting Information Available: Experimental procedures for
preparation of derivatives 2a-e (Scheme 1) (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA005704N
(8) Warpehoski, M. A.; Gebhard, I.; Kelly, R. C.; Krueger, W. C.; Li, L.
H.; MacGroven, J. P.; Prairie, M. D.; Wicnienski, N.; Wierenga, W. J. Med.
Chem. 1988, 31, 590-603.