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JSM Chemistry

Heterocyclic substituted 9-Anilinoacridines as Topoisomerase II Inhibitors

Editorial | Open Access Volume 6 | Issue 1 |

  • 1. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, India
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Corresponding Authors
Kalirajan Rajagopal, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Udhagamandalam, Tamilnadu, India, Tel: 91-4232443393; Fax: 91-42324432937
Citation

Rastogi K, Chang JY, Pan WY, Chen CH, Chou TC, et al. Antitumor AHMA linked to DNA minor groove binding agents: synthesis and biological evaluation. J Med Chem. 2002; 45: 4485-4493.

Editorial

9-anilinoacridines play an important role in the field of antitumor DNA-intercalating agents [1], due to their antiproliferative properties. Several anticancer agents with 9-anilinoacridines such as amascrine, and nitracrine have been developed. These agents are able to crosslink cellular DNA and thereby interfere with the DNA replication by inhibiting DNA topoisomerase II (topoII). Generally, topo II inhibitors are showing significant anticancer activity. Their strong activity was due to the ability of acridine nucleus to intercalate into DNA base pair, stabilizing the DNA-topoII cleavable complex ‘ternary complex’ which involves DNA, intercalated compound and topo II [2].

However, because of their high reactivity, they are biologically unstable because both Amsacrine (m-AMSA) and CI-921 possess a methane sulfonyl and a methoxy function at C-1’ and C-3’ of the 9-anilino ring and readily undergo reversible oxidation either chemically or microsomally giving the quinonediimine and more than 50%of the dose is excreted as the glutathione conjugate. The half-life of m-AMSA in the presence of fresh mouse blood at 37°C is 30 min. To improve the drawbacks of 9-anilinoacridines, one effective strategy is to design and synthesize to overcome the above problems. Many research papers are reported about the topoisomerase inhibition activity of 9-anilinoacridines [3-9].

As a part of our ongoing research on searching new potent antitumor agents as topoisomerase II inhibitors, we have developed 9-anilinoacridine analogues bearing various heterocyclic residues like isoxazole, pyrazole, thiazine and oxazine on 9-anilinoacridine rings against topoisomerase II [10- 12]. The docking studies of the designed molecules against topo II (pdb id: 1ZXM) revealed that all the heterocyclic substituted 9-anilinoacridines have significant binding affinity towards topo II when compared to the standard drugs like ledacrine. The high binding affinities of the molecules are mainly due to their high lipophilic profile and formation of hydrogen bonding with receptor.

As a part of our ongoing research on searching new potent antitumor agents as topoisomerase II inhibitors, we have developed 9-anilinoacridine analogues bearing various heterocyclic residues like isoxazole, pyrazole, thiazine and oxazine on 9-anilinoacridine rings against topoisomerase II [10- 12]. The docking studies of the designed molecules against topo II (pdb id: 1ZXM) revealed that all the heterocyclic substituted 9-anilinoacridines have significant binding affinity towards topo II when compared to the standard drugs like ledacrine. The high binding affinities of the molecules are mainly due to their high lipophilic profile and formation of hydrogen bonding with receptor.

ACKNOWLEDGEMENTS

The authour thank our Vice Chancellor Dr.B.Suresh, JSS University, Mysuru, our principal Dr.S.P.Dhanabal, Department of Pharmaceutical analysis, Department of Pharmaceutical Biotechnology, Department of Pharmacology, JSS College of pharmacy, Ooty for the technical support.

REFERENCES

1. Rastogi K, Chang JY, Pan WY, Chen CH, Chou TC, et al. Antitumor AHMA linked to DNA minor groove binding agents: synthesis and biological evaluation. J Med Chem. 2002; 45: 4485-4493.

2. Adriana C, Giovanni M, Christine M, Lisa DV, Maria GF, Giovanni P, et al. Synthesis and antitumor activity of novel amsacrine analogs: The critical role of the acridine moiety in determining their biological activity. Bioorg Med Chem. 2009; 17: 523-529.

3. Zigao Yuan, Shaopeng Chen, Changjun Chen, Jiwei Chen, Chengken Chen, Qiuzi Dai, et al. Design, synthesis and biological evaluation of 4-amidobenzimidazoleacridine derivatives as dual PARP and Topo inhibitors for cancer therapy. European J Med Chem. 2017; 138: 1135- 1146.

4. Goodell JR, Madhok AA, Hiasa H, Ferguson DM. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg Med Chem. 2006; 14: 5467-5480.

5. Peng Yang, Qing Yang, Xuhong Qian. Novel DNA bis-inteclators of isoquinolino [4,5-bc] acridines: design, synthesis and evaluation of cytotoxic activities. Tetrahedron. 2005; 61: 11895-11901.

6. Spicer JA, Gamage SA, Atwell GJ, Finlay GJ, Baguley BC, Denny WA. Inhibitor N-[2-(dimethylamino) ethyl] acridine -4-carboxamide. J Med Chem. 1997; 40: 1919-1929.

7. Rajesh Kumar, Ankita Sharma, Sarita Sharma, Om Silakari, Mandeep Singh, Manmeet Kaur. Synthesis, characterization and antitumor activity of 2-methyl-9-substituted acridines. Arabian J Chem. 2017; 10: 5956-5963.

8. Bacherikov VA, Chang JY, Lin YW, Chen CH, Pan WY, Dong H, et al. Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives. Bioorg Med Chem. 2005; 13: 6513-6520.

9. Kalirajan R, Vivek kulshrestha, Sankar S, Jubie S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their anti oxidant and anticancer activities as topo isomerase ii inhibitors. Eur J MedChem. 2012; 56: 217-224.

10. Kalirajan R, Muralidharan V, Jubie S, Gowramma B, Gomathy S, SankarS, et al. Synthesis of some novel pyrazole substituted 9-anilino acridine derivatives,and evaluation for their antioxidant and cytotoxic activities. J Heterocycl chem. 2012; 49: 748-754.

11. Kalirajan R, Gowramma B, Jubie S, Sankar S. Molecular Docking Studies and In silico ADMET Screening of Some Novel Heterocyclic Substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. JSM Chem. 2017; 5: 1039-1044.

12. Kalirajan R, Sankar S, Jubie S, Gowramma B. Molecular Docking studies and in-silico ADMET Screening of Some novel Oxazine substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. Indian JPharm Educ Res. 2017; 51: 110-115

Cave DD, Ilisso CP, Mosca L, Pagano M, Martino E, et al. (2017) The Anticancer Effects of S-Adenosylmethionine on Breast Cancer Cells. JSM Chem 5(3): 1049.

Received : 07 Jul 2018
Accepted : 07 Jul 2018
Published : 09 Jul 2018
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