Dual Topo 1X11 Inhibitors

3.4.1 History. The topo I and topo II enzymes are expressed at different absolute levels in different cell types. Topo II levels are reported to be high in many breast and ovarian lines (233), whereas topo I levels are reported to be high in many colon cancer lines (234); the good clinical activity of camptoth-ecin analogs against colon tumors has been suggested because in part of this high level of topo I expression (235). The time-course of expression of topo I and topo II also differs markedly, with topo II levels at their highest during S-phase, whereas levels of topo I remain relatively constant through the cell cycle (236). Because expression of either enzyme seems to be sufficient to support cell division, the development of resistance to topo I inhibitors is often accompanied by a concomitant rise in the level of topo II and vice versa (237,238).

Thus, one of the recent interests in topo inhibitors has been in agents capable of simultaneous inhibition of both enzymes, although relatively few compounds have been reported as dual topo 1/11 inhibitors (239). The anthra-quinone saintopin (48) is a potent poison of both topo I and topo II (240) but has not been developed as a drug. The quaternary alkaloid nitidine (49)is reported (241) t o be a dual poison, although more active against topo I. The related quaternary salt NK 109 (50) is described as a topo II poison, but etoposide-resis-tant lines with reduced topo II levels are still sensitive (242), suggesting a dual activity. Most work has been focused on the DNA in-tercalators DACA (51;XR-5000), intoplicine (52), and TAS 103 (53).

(48)
(52)

The 9-aminoacridine-4-carboxamides were first reported in 1984 as a new class of DNA-

intercalating agents (243) with well-defined structure-activity relationships for both chro-mophore and side-chain (244). The derived acridine-4-carboxamide analog (51) (DACA) also binds to DNA by intercalation and induces DNA cleavage in the presence of either topo I or topo II enzymes, being unaffected by either P-glycoprotein-mediated multidrug resistance or "atypical" multidrug resistant caused by low topo II activity (245). DACA showed remarkable activity against multidrug resistant cells (246) and in vivo activity against the Lewis lung carcinoma (247), leading to clinical evaluation.

The DNA-intercalating (248) pyridoindole intoplicine (52) is reported to also be a dual topo I/II poison (248, 249). Analogs of intoplicine that were only topo I or topo II poisons were less cytotoxic (248), suggesting the possible use of a dual poisoning ability. Intoplicine showed activity in a variety of human tumor explants in a soft agar cloning assay and in transplantable mouse tumors in vivo (251). Phase I trials of intoplicine have been conducted (252,2531, but phase II trials have not been reported.

The indenoquinolone TAS-103 (53)is also reported to be a DNA-intercalating agent

(254) and to enhance both topo I- and topo 11-mediated DNA cleavage in treated cells

(255), but it is now considered that topo II is the primary cellular target (256). TAS-103 showed broad-spectrum activity against a number of cell lines, with no cross-resistance in cells with lower topo I expression and only slight cross-resistance in those where topo II was down-regulated (257). A phase I clinical trial of TAS 103 recommended a dose of 130160 mg/m2 for phase II trials (258), but these have not yet been reported.

3.4.2 Mechanism and SAR. There seems to be no clear structural features predisposing to dual topo I/II activity. Raman and CD studies of intoplicine analogs suggest that the dual poisoning abilities of intoplicine are a result of its ability to simultaneously form two types of DNA complexes: a "deep intercalation mode" responsible for topo I-mediated cleavage and an "outside binding mode" responsible for topo 11-mediated cleavage (259).

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