Stereo(C7)‐dependent Topoisomerase II Inhibition and Tumor Growth Suppression by a New Quinolone, BO‐2367

Yoshinari, Tomoko; Mano, Eiichi; Arakawa, Hiroharu; Kurama, Masae; Iguchi, Tomoko; Nakagawa, Susumu; Tanaka, Nobuo; Okura, Akira

doi:10.1111/j.1349-7006.1993.tb02047.x

Cited by 8 publications

(3 citation statements)

References 14 publications

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“…This method has been particularly useful in the detection of covalent binding of topo I and II to DNA. Because the detection of the DNA-topo covalent complex involved in the DNA unwinding process is greatly enhanced by topo inhibitors that can result in the trapping of the reaction (covalent) intermediate, the screening of topo enzyme inhibitors is also facilitated by this method (20). In our experiments, […”

Section: Resultsmentioning

confidence: 99%

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Martínez

Owa

Schreiber

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

168

102

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A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC 50 ‫؍‬ 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin-and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.Ecteinascidin 743 (Et 743) is an exceedingly potent antitumor agent isolated from extracts of the marine tunicate Ecteinascidia turbinate that is currently undergoing phase II clinical trials as a result of its promising efficacy in preclinical antitumor tests (1-5). Although the detailed molecular mechanism of action still remains unclear, Et 743 has been reported to yield DNA sequence-selective alkylation of guanine N2 in the minor groove of duplex DNA (6). Additionally, bioassays for antimetabolic activities and enzyme inhibitions revealed Et 743 showed potent inhibition of DNA and RNA synthesis and of RNA polymerase activity but much less inhibition of DNA polymerase activity (7). Despite the minute human dosage of Et 743 currently being used in the clinic, Ϸ2 mg per person by i.v. infusion, the supply of this rare natural product is inadequate for large-scale studies. Consequently, a multistep total chemical synthesis has been developed to provide the amounts of Et 743 required for medical use (8). The availability of this synthetic process and the desirability of finding simpler and more stable structural relatives of Et 743 has led us to synthesize and evaluate new members of this class of substances. Described herein is the discovery of a number of compounds that significantly exhibit antitumor activity. The most potent of these, phthalascidin (Pt 650, Fig. 1

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Section: Resultsmentioning

confidence: 99%

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Martínez

Owa

Schreiber

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

168

102

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“…Following the realization that prokaryotic and eu- karyotic topoisomerases acted through similar mecha- nisms, Banyu (in collaboration with Merck) screened a  set of its experimental antibacterial quinolones against  mammalian topo II [201, 202]. In so doing, Banyu  identified (-)-BO-2367 ( 116 ) as a potent topo II inhibi- tor of DNA relaxation more active than etoposide in  that biochemical assay (3.8 μM vs 7.4μM, respectively)  and which prevented tumor growth in mice (Tables 16  and 17 ).…”

Section: Banyu/merck Sarmentioning

confidence: 99%

A “Double-Edged” Scaffold: Antitumor Power within the Antibacterial Quinolone

Bisacchi

Hale²

2016

CMC

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In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today’s predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents.

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“…SEGEV and E. RUBINSTEIN BO-2367 strongly inhibited both mammalian and bacterial topoisomerase II (YOSHINARI et al 1993). SEGEV and E. RUBINSTEIN BO-2367 strongly inhibited both mammalian and bacterial topoisomerase II (YOSHINARI et al 1993).…”

Section: Absorptionmentioning

confidence: 99%

Quinolone Antibacterials

1998

Handbook of Experimental Pharmacology

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Stereo(C7)‐dependent Topoisomerase II Inhibition and Tumor Growth Suppression by a New Quinolone, BO‐2367

Cited by 8 publications

References 14 publications

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

A “Double-Edged” Scaffold: Antitumor Power within the Antibacterial Quinolone

Quinolone Antibacterials

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