Piroxantrone is one of a series of compounds commonly known as anthrapyrazoles developed in an effort to combine the broad antitumor activity of the anthracyclines with decreased myocardial toxicity. The mechanism of action of piroxantrone and other anthrapyrazoles is incompletely understood but likely involves DNA binding with induction of DNA strand breaks, DNA-protein cross-linking, and inhibition of DNA, RNA, and protein synthesis. Collectively, these findings suggested an interaction with topoisomerase II. Piroxantrone demonstrated antitumor activity in a wide spectrum of experimental systems against breast carcinoma, colon carcinoma, sarcoma, melanoma and leukemia. Piroxantrone is inactive in patients with persistent, progressive, or recurrent ovarian cancer who recently had received a platinum-based regimen. Piroxantrone has detectable but minimal activity against disseminated malignant melanoma. A phase II clinical trial of the piroxantrone administration for the treatment of advanced metastatic or recurrent endometrial cancer was prematurely terminated due to lack of patient accrual.

Esorubicin (4'-deoxydoxorubicin, NSC 267469) is a synthetic derivative of the anthracycline antineoplastic antibiotic doxorubicin with potential antineoplastic activity. Esorubicin intercalates into DNA and inhibits topoisomerase II, thereby inhibiting DNA replication and ultimately, interfering with RNA and protein synthesis. This agent exhibits less cardiotoxicity than the parent antibiotic doxorubicin, but may cause more severe myelosupression compared to other compounds within the anthracycline class. Esorubicin was being clinically tested for the treatment of solid tumors as well as lymphomas an leukemias. Esorubicin development has been discontinued.

Crisnatol is a derivative of arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models. Crisnatol functions as a DNA intercalator, with the presence of additional basic amine groups in the sidechain enhancing binding to DNA due to electrostatic interactions. Crisnatol did not show antitumor efficacy in patients with ovarian carcinoma. In another clinical study, 2 of 26 patients with glioma showed complete long-lasting responses to the drug. The dose-limiting side effect was neurotoxicity.

Proflavine is an acriflavine derivative used as a topical disinfectant agains gram-positive bacteria. Proflavine is toxic and carcinogenic in mammals and so it is used only as a surface disinfectant or for treating superficial wounds. Proflavine acts by interchelating DNA (intercalation), thereby disrupting DNA synthesis and leading to high levels of mutation in the copied DNA strands. This prevents bacterial reproduction. Proflavine was investigated for photodynamic theraphy of herpes but was discontinued due to several presentations of post-treatment Bowen's disease and higher lesion recrudescence periods. Proflavine is also investigated as a topical contrast agent for imaging and diagnosis of esophageal, oral, colon, cervical, uterine cancer and polyps.

Aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects. Although its mechanism of action is incompletely defined, amsacrine inhibits DNA synthesis by binding to and intercalating with DNA. Amsacrine also inhibits topoisomerase II activity and may exert an effect on cell membranes. This agent also possesses immunosuppressive and antiviral properties. While amsacrine is not cell cycle phase-specific, cytotoxicity is maximal during the G2 and S phases.

Stallimycin also known as distamycin A is an antibacterial and antitumor compound. It is able to bind to the minor groove of double-stranded B-DNA in a non intercalative manner, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicles for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself.

Amrubicin is a totally synthetic 9-aminoanthracycline anticancer drug, which is approved in Japan for the treatment of small cell and non-small cell lung cancer. Upon administration amrubicin is reduced to its C-13 hydroxy metabolite, amrubicinol. The cytotoxicity of amrubicinol in vitro is 10 to 100 times greater than that of amrubicin. Thus, the anticancer activity of amrubicin is considered to derive from this active metabolite. The mechanism of action of the drug is related to the inhibition of topoisomerase II by stabilizing the cleavable complex.

Acodazole is a synthetic imidazoquinoline with antimicrobial and antineoplastic activity. Acodazole intercalates into DNA, resulting in disruption of DNA replication. Use of this agent has been associated with significant cardiotoxicity, especially prolonged cardiac output interval (Q-Ti) on electrocardiogram and polymorphic ventricular tachycardia ("torsades des pointes").

Zorubicin is a benzoylhydrazone derivative of the anthracycline antineoplastic antibiotic daunorubicin, but it introduces lower cardiomyopathy and bone marrow toxicity. Zorubicin intercalates into DNA and interacts with topoisomerase II, thereby inhibiting DNA replication and repair as well as RNA and protein synthesis. The cytotoxic effect results from intercalation between DNA pairs. To minimize toxicity, individualized dose regimens are given preferentially over prolonged periods of time by carefully inspecting i.v. administration to prevent extravasation.

Pixantrone is a novel anthracenedione. It is a weak inhibitor of topoisomerase II. Pixantrone directly alkylates DNA forming stable DNA adducts and cross-strand breaks. Pixuvri is approved for the treatment of adult patients with multiply relapsed or refractory aggressive Non-Hodgkin lymphomas. It is used for patients whose cancer does not respond or has returned after they have received other chemotherapy treatments. The most frequent AE were seen in the blood (mainly neutropaenia), gastrointestinal (nausea, abdominal pain, constipation) and respiratory systems (cough, dyspnea). No drug-drug interaction studies have been submitted and no drug interactions have been reported in human subjects