structure of a new topoisomerase ii inhibitor be 10988
TRANSCRIPT
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Tekahednm Lams, Vol.32, No.24. pp 2791-2792 1991
Printed in Great Britain m40-4039/91 $3.00 + .oa Pergm Press plc
STRUCTURE OF A NEW TOPOISOMERASE II INHIBITOR BE 10988
Hiroyuki SUDA*, Kimihiro MATSUNAGAt, Shosuke YAMAMURAt, and Yoshikazu SHIZURItt*
En;ploratory Research Laboratories, Banyu Pharmaceutical Co. Ltd., I-9-3 Shimomeguro, Meguro-ku, Tokyo
fDepartment of Chemistry, Faculty of Science’%i%%ology, Keio University, Hiyoshi, Kohoku-ku. Yokohama 223, Japan
f fFaculty of Pharmaceutical Sciences, Tokusima Bunnri University, Yamashirocho, Tokusima 770, Japan
Summary: The structure of a new topoisomerase II inhibitor BE 10988 was elucidated by using a long-range
selective proton decoupling expetiment coupled with some chemical evidence.
In the course of our screening program for new topoisomerase inhibitors from the culture broth, a new
antibiotic BE 10988 was isolated. This compound BE 10988 showed significant inhibitory activity against both
adriamycin or vincristine resistant P 388 mutine leukemia cell as well as sensitive P 388 cell line.1) Furthermore,
by means of a cell free K/SDS assay2) using purified topoisomerase I and II from L 1210 &Is and 3H-labelled E.
Coli DNA, BE 10988 specifically inhibited only topoisomerase II at a concentration of 3 CLglm. We report herein
the structural elucidation of BE 10988.
BE 10988 with a molecular fonnura C 13Hlo03NqS3) has the IR absorption bands at 3450.3390, 1662,
1620, 1590, 1540 and 1500 cm-*, and the UV absorption bands at 213,280,385, and 503.5 nm. Its 1H and
13C NMR spectral data are shown in Fig. I. As seen in Fig. I, BE 10988 has only six singlets in the 1~ NMR
spectrum, which gave us almost no information about the adjacent carbon atoms to these protons. Thus, great
efforts have been done to make crystals suitable for an X-ray analysis, but were unsuccessful. Therefore, a
detailed long-range selective proton decoupling experiment has been used for the structural elucidation.
1 BE 10988
Fig. I Long-range couplings based on long-range selective proton decoupling experiments
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From the results shown in Fig. I together with consideration of the absorption bands in UV spectrum, the
structure (1) was assigned for BE 10988. This structure. was further supported by long-range selective proton
decoupling experiments of the pentamethyl derivative E2)4) fomed on methylation‘of BE 10988 (MeI. NaH in
DMF, r.t.,12h). In this derivative, long-range couplings are observed between amide carbonyl group (164.2) and
two N-Me groups (3.18 and 3.31 each 3H, s), and between one carbon atom bearing nitrogen (152,6) and N-
(Me)2 group (3.22, 6H, s). Furthermore, in 1 no information was obtained about the connectivity of one
quinone carbonyl(177.6), but instead long-range couplings between this carbonyl group (177.2)
at 5.41 and 7.51 were observed in 2.
Fig. II 2 Pentamethyl derivative
Long-range couplings based on long-range selective proton decoupling experiments
and two protons
To confirm the proposed structure (I), Pentamethyl derivative (2) was reduced with Raney Ni in EtOH under
H2 to afford the aldehyde (3)s) , from which the alcohol (4)s) was obtained on reduction with NaBH4. As
judged from the NOE experiments (Fig III), finally, the position of the thiazole moiety in 1 was dewmined as
shown in Fig I. This structure was further confirmed by total synthesis.7)
2 2LMe~N+Q?ELM~N+~ Ra Ni
3 4 9.2%
Fig. III
Footnotes and rtieredces 1) Submitted for publication in J. Antibiot. 2) W. E. Ross, DNA topoisomerase as targets for cancer therapy. Biochem. Pburm.. 34.4191 (1985). 3) 1 as darkred crystals : mp >300“; Cl3Hl003NqS [m/z 302.051 l(M+)] ; Anal, Found: C,48.91; H,3.88;
N,17.82, Calcd for Cl3Hl003NqSH20: C, 48.75; H, 3.75; N, 17.50. 4) 2 as darkred crystals: Cl7Hl803N4S [m/z 359.1188 (M+l)]; IR, 1618,1560,1530,1510cm-1. 5) 3 as a red amorphous powder : Cl2Hl2N203 [m/z 232.0894 (M+)] ; IR, 1680,1660,1605,1595,1590,
1565. 1520 cm-l; lH NMR 3.22 (6H, s), 4.02 (3H, s), 5.41 (lH, s), 7.36 (1H. s), 10.37 (lH, s). 6) 4 as a red amorphous pow&r : Cl2Hl4N2O3 [m/z 234.0977 (M+)] ; IR, 3400,1660,1610,1565,1550,
1510 cm-l; 1H NMR 3.19 (6H, s), 3.93 (3H, s), 3.94 (lH, t, J=6.4 Hz, OH), 4.60 (2H, d, J=6.4 Hz), 5.35 (lH, s), 6.59 (1H. s).
7) Total synthesis of BE 10988 (1) will be reported elsewhere.
(Received in Japan 24 January 1991)