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Increasing antitumor activity in vivo by enhancing acridine dimer solubility with salt preparations

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Abstract

The potent activities of many anticancer agents have been demonstrated by in vitro assays. However, their poor solubility may result in diminishing anticancer activities in vivo. Previously, we synthesized a series of bisacridine derivatives shown to be potent in cytotoxicity and DNA intercalating activity in vitro. Initially, the compound 1, (N-(6-chloro-2-methoxy-acridin-9-yl)-N′-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-propane-1,3-diamine), is insoluble in polar solvent and does not reveal antihuman COLO 205 solid-tumor activity in vivo. To enhance its solubility, three salt forms (CH3COOH, CH3SO3H, and CF3COOH) of compound 1 were synthesized and their solubility was found to be greatly improved compared with that of the free base. Among these salts, the compound 1 · (tris)acetate salt has shown good solubility in H2O and 2.5% Cremophor (v/v) and demonstrated anti-COLO205 solid-tumor activity in vivo.

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Scheme 1
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Abbreviations

Compound 1 :

N-(6-Chloro-2-methoxy-acridin-9-yl)-N′-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-propane-1,3-diamine

Compound 2 :

Compound 1 · 3CH3COOH

Compound 3 :

Compound 1 · CH3SO3H

Compound 4 :

Compound 1 · 3CF3COOH

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Acknowledgements

The authors thank the Ministry of Economic Affairs, ROC. for financially supporting this research under Project No. MOEA 84-2-3 and MOEA 85-2-3. We also thank Dr. Brian Milbrath for reviewing the article.

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Authors and Affiliations

  1. Department of Chemical and Biochemical Engineering, Kao Yuan University, 1821 Chung-Shan Road, Lu-Chu Hsiang, Kaohsiung, Taiwan, ROC

    Shan-Shue Wang

  2. Bridging Global Tech Co., No 610, Sec. 2, Jhongsing Road, Meinong Township, Kaohsiung County, 843, Taiwan, ROC

    Shan-Shue Wang & Chen Hsieh

  3. Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC

    Yi-Jen Lee & Shih-Chung Hsu

  4. Department of Child Care and Education, Kang-Ning Junior College of Medical Care and Management, 137, Lane 75, Sec. 3, Kang-Ning Road, Nei-Hu, Taipei, Taiwan, ROC

    Shih-Chung Hsu

  5. School of Business, Central South University, Chanssha, Hunan, People’s Republic of China

    Chen Hsieh

  6. Division of Pharmaceutics, Development Center for Biotechnology, 103, Lane 169, Kang Ning Street, Xizhi City, Taipei, Taiwan, ROC

    Lien-Shange Chang & Shan-Yen Chou

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  1. Shan-Shue Wang
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  2. Yi-Jen Lee
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Correspondence to Shan-Shue Wang or Shan-Yen Chou.

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Wang, SS., Lee, YJ., Hsu, SC. et al. Increasing antitumor activity in vivo by enhancing acridine dimer solubility with salt preparations. Med Chem Res 19, 565–575 (2010). https://doi.org/10.1007/s00044-009-9213-9

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  • DOI: https://doi.org/10.1007/s00044-009-9213-9

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