Bn80927

BN-80927 (29) is a homocamptothecin and a potent topo I poison, but also a catalytic inhibitor of topo II.154,155 It has excellent cytotoxicity against a number of human tumor cell lines in culture (e.g., IC50 of 6.6 and 3 nM in HT29 colon and DU-145 prostate cell lines respectively).156 BN-80927 was more potent than SN38 (6) in both wild-type and camptothecin-resistant tumor cell lines, and was highly effective in tumor xenografts of the human androgen-independent prostate tumors PC-3 and DU-145; clinical trials have been recommended155 but are not yet reported.

7.05.4.2 Deoxyribonucleic Acid Intercalators 7.05.4.2.1 Pyrazoloacridine

Pyrazoloacridine (PZA, PD-115934) (30) came from a program evaluating polycyclic heterocycles as DNA intercalating agents, and was selected for its outstanding activity in solid tumor compared with leukemia models.157 It is a potent inhibitor of the catalytic activity of both topo I and topo II enzymes,158 but without stabilization of the topo-DNA cleavable complexes,159 suggesting an unusual mechanism of action. It is also a hypoxia-selective agent,160 with bioreduction of the 5-nitro group likely to form transient alkylating species. In support of the latter point, the corresponding 5-amino derivative is a major metabolite in mice.161 The three main oxidative metabolites of PZA in mice were 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide; studies with a panel of cloned enzymes and inhibitors showed that 9-desmethyl-PZA was largely produced by CYP1A2, N-demethyl-PZA formation by CYP3A4, and PZA N-oxide by flavin monooxygenase. PZA N-oxide and N-demethyl-PZA were detected in urine from patients after PZA administration.162 Pyrazoloacridine has received extensive clinical trial because of its broad-spectrum activity in animal solid tumor models,160 and its novel mechanism of action, but was inactive in many Phase II trials.163 More recently, PZA was shown to be highly cytotoxic in a series of multidrug-resistant neuroblastoma cell lines, suggesting it may be effective clinically against neuroblastoma.164 However, a recent Phase II study of a PZA/carboplatin combination in patients with recurrent glioma showed only modest activity, with short-term disease stabilization in about 38% of the patients.165

XR-11576 (31) is a lipophilic benzo[a]phenazine derivative, developed from earlier work on benzophenazinecarbox-amide intercalators.166 Detailed SAR studies167 established the 4-methoxybenz[a]phenazine-11-carboxamide series as the most potent, and led to selection of the R-methyl enantiomer XR-11576 for clinical development (the first chiral synthetic DNA intercalating agent to be brought to clinical trial). It is a dual inhibitor of topo I and IIa in enzyme assays, inducing cleavable complex formation by both at concentrations as low as 30 nM. XR-11576 is a potent cytotoxin in a range of murine and human cell lines, with the activity being unaffected by either transport resistance mechanisms or by atypical drug resistance generated by low topo IIa levels.168 It showed significant and comparable activity against subcutaneous HT29 human colon tumor xenografts in mice using either intravenous (52.5 mgkg_ 1) or oral (75 mgkg_ 1) dosing on days 1-5, repeating every 21 days.168 A Phase I trial giving drug orally on days 1-5 every 3 weeks identified the maximum tolerated dose as 180 mg per day, with diarrhea and fatigue as the major toxicities, although extensive support antiemetic therapy was also needed.169

MLN-944 (32) is in the same broad structural class as elinafide (see above). It binds tightly (Ka = 1.6 x 109M_ 1) to DNA by intercalation, preferentially to GC-rich regions, suggesting a binding mode with the linker chain lying in the major groove.170 This was confirmed by an NMR structure of MLN-944 complexed with the DNA duplex d(ATGCAT)2 showing the two phenazine rings intercalate at the 5'-TpG sites, with the linker chain lying in the major groove of DNA.171 It was the most potent (IC50 of 0.08 nM in human leukemia cells) of a series of compounds reported to be dual topo I/II inhibitors and potent cytotoxins,172 and was shown to stabilize cleavable complex formation between DNA and both topo I and human topo IIa, with fragmentation patterns different to that generated by the specific inhibitors etoposide and camptothecin.173 Later electrophoretic gel mobility shift studies showed that MLN-944 significantly inhibited c-Jun DNA binding to the AP-1 site.171 Studies in synchronized human HCT 116 cells showed MLN-944 induced G1 and G2 arrest, unlike the typical G2-M arrest noted with known topoisomerase poisons. Transcriptional profiling analysis of treated xenografts showed clusters of regulated genes distinct from those observed in irinotecan-treated tumors. This suggested that the primary mechanism does involve DNA binding, but not topoisomerase inhibition.174 More generally, MLN-944 inhibited transcription initiation of all RNA polymerases, as well as inhibiting transcription elongation at higher concentrations, suggesting that transcription is the primary target, and is the reason for its high cytotoxicity.175 In vivo, MLN-944 induced regressions of both HT29 and H69/P xenografts, inducing 100% cures in the latter model at an intravenous dose of 5 mgkg_ 1 on a daily schedule.173 Phase I clinical trials are in progress, but have not been formally reported on.

7.05.4.3 Epipodophyllotoxins

7.05.4.3.1 Tafluposide

Tafluposide (F11872) (33) is a novel phosphate prodrug of a lipophilic, perfluorinated epipodophyllotoxin, and is an example where significant modification of a topo II inhibitor has altered its spectrum of enzyme activity. Tafluposide has superior antitumor activity in vivo compared to etoposide.176 Although it does not inhibit the religation step of the catalytic cycle of either topo I or topo II, it is a potent inhibitor of the catalytic activities of both enzymes. It does not bind to DNA, but inhibits the binding of the enzymes to DNA in a drug- and enzyme-dependent manner177 and possibly represents a new class of topoisomerase agent. A resistant P388 leukemia subline retained marked collateral sensitivity to cisplatin, topotecan, colchicine, and Vinca alkaloids, with no overexpression of resistance-related proteins or modification of the glutathione-mediated detoxification process. However, nucleotide excision repair activity was decreased threefold, suggesting that both topoisomerase IIa and DNA repair enzymes are major targets.178 Tafluposide showed exceptionally high in vivo activity across a variety of tumor models, including P388 leukemia and B16 melanoma, and MX-1 and LX-1 xenografts, with an unusually broad therapeutic range.179 It shows synergistic effects in the A549 human nonsmall cell lung cancer line in culture with cisplatin, etoposide, doxorubicin, and mitomycin C,180 and activity against early passage cell lines from cancer patients.181 The drug has been advanced to clinical trial, but results have not yet been reported.

Quit Smoking Today

Quit Smoking Today

Quit smoking for good! Stop your bad habits for good, learn to cope with the addiction of cigarettes and how to curb cravings and begin a new life. You will never again have to leave a meeting and find a place outside to smoke, losing valuable time. This is the key to your freedom from addiction, take the first step!

Get My Free Ebook


Post a comment