Molecular recognition and enhancement of aqueous solubility and bioactivity of CD437 by β-cyclodextrin

Abstract

CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) is a novel synthetic retinoic acid derivative that has been shown to selectively induce apoptosis in human lung cancer cells. This compound, however, is limited in its application due to its low solubility in aqueous solutions. One technique for increasing the solubility and bioavailability of a cytotoxic agent is the formation of inclusion complexes with cyclodextrins. Herein, we report the formation and characterization of a 2:1 complex between β-cyclodextrin (β-CD) and CD437. It is shown that CD437 is a tight binder of β-CD with an overall association constant of 2.6 ± 0.6 ×10 7 M −2 . In addition, we demonstrate (a) that β-CD-derived complexation enhances the aqueous solubility of CD437, and (b) that a significant increase in the toxicity of CD437 against a human lung adenocarcinoma cell line can be achieved by co-treatment with β-CD. Keywordscyclodextrin; inclusion complex formation; supramolecular chemistry; anticancer agent CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) is a synthetic retinoic acid (RA) derivative which is known to have antineoplastic properties across a variety of cancer cell lines, including lung, 1 prostate, 2 ovarian, 3-4 cervical, 5 and head and neck. 6 Typically, the molecular action of retinoids depends on the binding to and activation of a subset of the nuclear hormone receptor superfamily which contains both retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each of which is encoded by three genes, α, β, and γ. CD437, like RA, can bind directly to a heterodimer formed between retinoic acid receptor γ (RARγ) and a retinoid X receptor (RXR). Growth arrest and cell differentiation then occur when the activated RARγ/RXR dimer binds to a RA response element on DNA. 7 In contrast to RA, however, CD437 also displays strong apoptotic properties. In addition to the RARγ-dependent pathway, CD437 is also able to exert its * Corresponding Author: J. Jayawickramarajah, Tel.: +01-504-862-3580, Fax: +01-504-865-5596, jananj@tulane.edu. † Department of Medicine ‡ Department of Chemistry Supplementary data Supplementary data associated with this article can be found, in the online version, at xxx Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript apoptotic effects through an RARγ-independent pathway. 8 Thus CD437 has been shown to induce apoptosis in both RA-resistant cell lines [8][9] and RARγ-negative cell lines. 8,10 Despite the significant anti...

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“…According to the literature, phase solubility analysis is one of the preliminary requirements for developing a drug/cyclodextrin inclusion complex as it permits an evaluation of the affinity between the drug molecule and cyclodextrin (21). Many researchers have used this approach to determine the molar ratio in which a drug can form a complex with cyclodextrins (11)(12)(13)(14). However, the phase solubility profiles do not demonstrate the formation of inclusion complexes; they only describe how the increasing cyclodextrin concentration influences drug solubility.…”

“…A greater number of reports mentioned the use of cyclodextrins in the formation of inclusion complexes with hydrophobic drugs, including acridine derivatives, for enhancement of their solubility (9)(10)(11)(12)(13)(14).…”

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…SHP, the probable target protein of the adamantyl retinoids, also is of significance in metabolic anormalities such as diabetes, fatty liver, and insulin resistance; therefore, SHP regulation is a valuable goal in these fields also. 846 Development of further, selective SHP ligands, therefore, surely is warranted; together with advancements in overcoming the intrinsically low solubilities of most of the adamantyl retinoids in aqueous media via, e. g., formation of β-cyclodextrin complexes as has been successfully shown for 403 , 847 further pre-clinical and clinical drug development in the field of adamantyl retinoids is to be expected.…”

Cyclodextrins and ternary complexes: technology to improve solubility of poorly soluble drugs

“…This allows the construction of three-dimensional models of drug-CD complexes, visualization of structural integrity, and intra-and intermolecular interactions (Seridi, Boufelfel, 2011;Leila et al, 2011;Eid et al, 2011;Ge et al, 2011;Mishur et al, 2011).…”