Rational Design, Synthesis, and Biological Evaluation of Bis(pyrimido[5,6,1-de]acridines) and Bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as New Anticancer Agents

Abstract

The good results obtained with pyrimido[5,6,1-de]acridines 7 and with pyrazolo[3,4,5-kl]acridinecarboxamides 8 prompted us to the synthesis of two new series of bis acridine derivatives: the bis(pyrimidoacridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the bis derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and (iv) in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure-activity relationships are discussed. We could identify six very potent cytotoxic compounds for further in vitro studies: a cytotoxic screening against six human cancer cell lines and the National Cancer Institute (NCI) screening on 60 human tumor cell lines. Finally, compound 6a was selected for evaluation in a NCI in vivo hollow fiber assay.

Molecular Symmetry: A Structural Property Frequently Present in New Cytotoxic and Proapoptotic Drugs

“…Furthermore, the shortest linker gives rise to a lower cytotoxicity and DNA affinity with respect to the longest linker. These results are valid when the acridine possesses a fused pyrazole or pyrimido ring [71]. Furthermore, Wakelin [72] completed the study with semirigid chains (piperazine) as the linker and a morpholino unit in the carboxamide.…”

“…8 [70][71][72] studied related structures and confirmed that the bisacridone derivatives are more active than the corresponding monomers. Furthermore, the shortest linker gives rise to a lower cytotoxicity and DNA affinity with respect to the longest linker.…”

Use of the in Vivo Hollow Fiber Assay in Natural Products Anticancer Drug Discovery

“…The hollow fiber assay has been incorporated into the drug discovery programs of many laboratories around the world including Argentina,69 Austria,70 France,71 Germany,72 India,73Italy,74–78 New Zealand,79 Poland,80,81 Spain,82,83 Sweden,84 and the United Kingdom 85–89…”

Dimeric Approaches to Anti-Cancer Chemotherapeutics

“…The most active compounds identified from this study resulted in highly cytotoxic molecules that exhibited IC 50 values against HT-29 cells at low or subnanomolar concentrations ( 17 , 18a , and 18b ). Second generation ‘cyclized’ acridone carboxamides ( 19 , 20a , and 20b ) were generally poorer DNA binders than the corresponding ‘open’ analogues and possessed a preference for AT-rich sequences; however, they continued to maintain low to subnanomolar cytotoxic activity [68]. Preliminary in vivo results from a hollow fiber assay demonstrated that 19 exhibited in vivo activity worthy of further testing in xenograft models, which are currently underway.…”