1 Vìsnik Dnìpropetrovs’kogo unìversitetu. Serìâ hìmìâ ͸͸ ȋ͸ͶͷͺȌ, 2, 1–20 ʑі˔ːˋˍ ʓːі˒˓ˑ˒ˈ˕˓ˑ˅˔˟ˍˑˆˑ ˖ːі˅ˈ˓˔ˋ˕ˈ˕˖. ʠˈ˓іˢ ʤіˏіˢ Bulletin of Dnipropetrovsk University. Series Chemistry p-ISSN 2306-871X, e-ISSN 2313-4984 journal homepage: http://chemistry.dnu.dp.ua UDC 577.181.7:542.913:616-006:577.164.1 9-ANILINOACRIDINES AS ANTICANCER DRUGS Valeriy A. Bacherikov * OMI of International Humanitarian University, Fontanskaya Road, 23A, Odessa, 65009, Ukraine Received 23 August 2014; revised 30 September 2014; accepted 11 November 2014, available online 11 December 2014 Abstract The information about the structures, synthesis and biological activity of 9-anilinoacridines, highly active anticancer drugs studied in the last decade was reviewed. Structure – property relationships of the leading compounds 4’-(9-acridinylamino)- metansulfon-m-anisidine (m-AMSA) and 3-(9-acridinylamino)-5-hydroximethylaniline (AHMA), their mechanism of biological action aimed at inhibition of the ternary complex of DNA – Topoisomerase II – Drug and mechanisms of their degradation and excretion were considered. Among the new derivatives of 9-anilinoacridine the hybrids of AHMA and DNA minor groove binding agents, such as Distamycin A or Netropsin, were discussed. Hybrid molecules able to interact with the DNA by anilinoacridine residue and inhibit topoisomerase II, as well as conjugate to the minor groove of DNA, should show significant increasing of selectivity and proper high activity, and will also less contribute to drug resistance in cancer cells. Investigation of biological activity of 5-(9-acridinylamino)-o, m, p-toluidines and 5-(9-acridinylamino)-o, m, p-anisidines, which were synthesized in order to design of an anticancer agent molecule having high activity and low toxicity, was considered. The modification of the 9-anilinoacridine molecule by the variety of substituents and linkers, and the synthesis and cytotoxicity of hybrid compounds composed from 9-anilinoacridine molecule and nitrogen mustards attached to aniline and acridine residues were discussed in details. Keywords: derivatives of 9-anilinoacridine; hybrid molecules; structure; antitumor activity; topoisomerase inhibitors; N-mustard alkylators. 9-ʏʜІʚІʜʝʏʙʟʗʓʗʜʗ Яʙ ʞʟʝʡʗʟʏʙʝʑІ ʞʟʔʞʏʟʏʡʗ ʑ˃ˎˈ˓іˌ ʏ. ʐ˃˚ˈ˓ˋˍˑ˅ * ОʛІ ʛ˪ˉː˃˓ˑˇːˑˆˑ ˆ˖ˏ˃ː˪˕˃˓ːˑˆˑ ˖ː˪˅ˈ˓˔ˋ˕ˈ˕˖, ʣˑː˕˃ː˔˟ˍ˃ ˇˑ˓ˑˆ˃, ͸͹А, ˏ. Оˇˈ˔˃, ͼͻͶͶͿ, ʢˍ˓˃˫ː˃ ʏːˑ˕˃˙іˢ ʑ ˑˆˎˢˇ˪ ˓ˑˊˆˎˢː˖˕ˑ ˪ː˗ˑ˓ˏ˃˙˪ˡ ˒˓ˑ ˔˕˓˖ˍ˕˖˓ˋ, ˔ˋː˕ˈˊ ˪ ˄˪ˑˎˑˆ˪˚ː˖ ˃ˍ˕ˋ˅ː˪˔˕˟ ˒ˑ˘˪ˇːˋ˘ ͻ-˃ː˪ˎ˪ːˑ˃ˍ˓ˋˇˋː˃, ˅ˋ˔ˑˍˑ˃ˍ˕ˋ˅ːˋ˘ ˒˓ˑ˕ˋ˒˖˘ˎˋːːˋ˘ ˒˓ˈ˒˃˓˃˕˪˅, ˅ˋ˅˚ˈːˋ˘ ˊ˃ ˑ˔˕˃ːːє ˇˈ˔ˢ˕ˋˎ˪˕˕ˢ. ʟˑˊˆˎˢː˖˕ˑ ˅ˊ˃єˏˑ˅˪ˇːˑ˔ˋːˋ ˔˕˓˖ˍ˕˖˓˃ – ˅ˎ˃˔˕ˋ˅˪˔˕˟ ˔ˈ˓ˈˇ ˎ˪ˇˋ˓˖ˡ˚ˋ˘ ˔˒ˑˎ˖ˍ – 4’-(9-˃ˍ˓ˋˇˋː˪ˎ˃ˏ˪ːˑȌˏˈ˕˃ː˔˖ˎ˟˗ˑː-м-˃ː˪ˊˋˇˋː˃ ȋм-AMʠAȌ ˪ ͵- (9-˃ˍ˓ˋˇˋː˪ˎ˃ˏ˪ːˑȌ-5-ˆ˪ˇ˓ˑˍ˔ˋˏˈ˕˪ˎ˃ː˪ˎ˪ː˃ ȋʏʒʛʏȌ, ˫˘ ˏˈ˘˃ː˪ˊˏ ˄˪ˑˎˑˆ˪˚ːˑ˫ ˇ˪˫, ː˃˙˪ˎˈːˋˌ ː˃ ˪ːˆ˪˄˖˅˃ːːˢ ˒ˑ˕˓˪ˌːˑˆˑ ˍˑˏ˒ˎˈˍ˔˖ ʓʜʙ – ʡˑ˒ˑ˪ˊˑˏˈ˓˃ˊ˃ )) – ʚ˪ˍˋ ˕˃ ˏˈ˘˃ː˪ˊˏˋ ˇˈˆ˓˃ˇ˃˙˪˫ ˪ ˅ˋ˅ˈˇˈːːˢ ˊ ˑ˓ˆ˃ː˪ˊˏ˖ ˙ˋ˘ ˒˓ˈ˒˃˓˃˕˪˅. ʠˈ˓ˈˇ ːˑ˅ˋ˘ ˒ˑ˘˪ˇːˋ˘ ͻ-˃ː˪ˎ˪ːˑ˃ˍ˓ˋˇˋː˃ ˑ˄ˆˑ˅ˑ˓ˈː˪ ˆ˪˄˓ˋˇˋ ʏʒʛʏ ˪ ˃ˆˈː˕˪˅, ˃˗˪ːːˋ˘ ˇˑ ˏ˃ˎˑ˫ ˄ˑ˓ˑˊˈːˍˋ ʓʜʙ, ˕˃ˍˋ˘ ˢˍ ˇ˪˔˕˃ˏ˪˙ˋː ʏ ˚ˋ ːˈ˕˓ˑ˒˔ˋː. ʞˈ˓ˈˇ˄˃˚˃ˎˑ˔ˢ, ˜ˑ ˆ˪˄˓ˋˇː˪ ˏˑˎˈˍ˖ˎˋ, ˊˇ˃˕ː˪ ˪ː˕ˈ˓ˍ˃ˎ˪˓˖˅˃˕ˋ˔ˢ ˊ ʓʜʙ ˊ˃ ˇˑ˒ˑˏˑˆˑˡ ˃ː˪ˎ˪ːˑ˃ˍ˓ˋˇˋːˑ˅ˑˆˑ ˗˓˃ˆˏˈː˕˃ ˪ ˪ːˆ˪˄˖˅˃˕ˋ ˕ˑ˒ˑ˪ˊˑˏˈ˓˃ˊ˖ )), ˕˃ˍ ˔˃ˏˑ ˢˍ ˪ ˍˑː'ˡˆ˖˅˃˕ˋ˔ˢ ˅ ˏ˃ˎ˖ ˄ˑ˓ˑˊˈːˍ˖ ʓʜʙ, ˅ˋˢ˅ˎˢ˕˟ ˒˪ˇ˅ˋ˜ˈː˖ ˖ ˄˃ˆ˃˕ˑ ˓˃ˊ˪˅ ˔ˈˎˈˍ˕ˋ˅ː˪˔˕˟ ˪ ˅˪ˇ˒ˑ˅˪ˇː˖ ˅ˋ˔ˑˍ˖ ˃ˍ˕ˋ˅ː˪˔˕˟, ˃ ˕˃ˍˑˉ ˄˖ˇ˖˕˟ ˏˈː˛ ˔˒˓ˋˢ˕ˋ ˅ˋːˋˍːˈːːˡ ˓ˈˊˋ˔˕ˈː˕ːˑ˔˕˪ ˅ ˓˃ˍˑ˅ˋ˘ ˍˎ˪˕ˋː˃˘. ʟˑˊˆˎˢː˖˕ˑ ˄˪ˑˎˑˆ˪˚ː˖ ˃ˍ˕ˋ˅ː˪˔˕˟ ˓ˢˇ˖ ͷ-(9-˃ˍ˓ˋˇˋː˪ˎ˃ˏ˪ːˑȌ-ˑ, м, ˒-˕ˑˎ˖˫ˇˋː˪˅ ˪ ͷ-(9-˃ˍ˓ˋˇˋː˪ˎ˃ˏ˪ːˑȌ -ˑ, м, ˒-˃ː˪ˊˋˇˋː˪˅, ˢˍ˪ ˄˖ˎˋ ˔ˋː˕ˈˊˑ˅˃ː˪ ˊ ˏˈ˕ˑˡ ˇˋˊ˃ˌː˖ ˏˑˎˈˍ˖ˎˋ ˒˓ˑ˕ˋ˓˃ˍˑ˅ˑˆˑ ˃ˆˈː˕˃ ˜ˑ ˏ˃є ˅ˋ˔ˑˍ˖ ˃ˍ˕ˋ˅ː˪˔˕˟ ˪ ːˋˊ˟ˍ˖ ˕ˑˍ˔ˋ˚ː˪˔˕˟. ʓˈ˕˃ˎ˟ːˑ ˑ˄ˆˑ˅ˑ˓ˈː˪ ˏˑˇˋ˗˪ˍ˃˙˪ˢ ˏˑˎˈˍ˖ˎˋ ͻ- ˃ː˪ˎ˪ːˑ˃ˍ˓ˋˇˋː˃ ˊ˃ ˇˑ˒ˑˏˑˆˑˡ ˓˪ˊːˑˏ˃ː˪˕ːˋ˘ ˊ˃ˏ˪˔ːˋˍ˪˅ ˕˃/˃˄ˑ ˎ˪ːˍˈ˓˪˅ ˕˃ ˔ˋː˕ˈˊ ˪ ˙ˋ˕ˑ˕ˑˍ˔ˋ˚ː˪˔˕˟ ˆ˪˄˓ˋˇːˋ˘ ˔˒ˑˎ˖ˍ ː˃ ˑ˔ːˑ˅˪ ͻ-˃ː˪ˎ˪ːˑ˃ˍ˓ˋˇˋː˃ ˪ ˃ˊˑ˕ˋ˔˕ˋ˘ ˪˒˓ˋ˕˪˅, ˒˓ˋєˇː˃ːˋ˘ ˇˑ ˃ː˪ˎ˪ːˑ˅ˋ˘ ˕˃/˃˄ˑ ˃ˍ˓ˋˇˋːˑ˅ˋ˘ ˗˓˃ˆˏˈː˕˪˅ ˏˑˎˈˍ˖ˎ. __________________________ * Corresponding author: Tel.: +380487581060; e-mail address: valeriy_bacherikov@yahoo.com © 2014 Oles Honchar Dnipropetrovsk National University doi: 10.15421/081416