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Azulenic retinoids: novel nonbenzenoid aromatic retinoids with anticancer activity
A E Asato1, A Peng, M Z Hossain
1Chemistry Department, University of Hawaii at Manoa, Honolulu 96822.
Abstract:
Several novel azulene-containing retinoids were prepared and evaluated for their ability to suppress carcinogen-induced neoplastic transformation and to concomitantly up-regulate gap junctional communication in the in vitro mouse fibroblast C3H/10T1/2 cell bioassay. The azulenic retinoids were divided into two groups: compounds 1-6 were modeled after retinoic acid with flexible polyenic side chain whereas retinoids 7-13 featured a benzoic acid moiety analogous to the prototypic retinobenzoate (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl]benzoic acid (TTNPB). Within this latter group the side chains for compounds 7, 10, and 11 were attached at the 1-, 2-, and 8-positions of the azulenic terminus, respectively. Biological activities were determined for all the new compounds. Two of these novel retinoids, azulenic retinobenzoic acid derivatives 7 and 11, were completely effective inhibitors of transformation at 10(-6) M. The most active azulenic retinoids also enhanced gap junctional communication in untransformed cells; this was associated with up-regulated expression of connexin 43, a structural protein of the gap junction. Two fluorinated analogs were also tested. The azulenic fluoro acid 5 was found to be more potent than the trifluoromethyl analog 6. Azulenic analogs with hydroxyl or carboxaldehyde side chain functional groups were ineffective transformation inhibitors. In general, azulenic retinobenzoic acid analogs structurally akin to TTNPB were more effective than flexible side chain analogs related to retinoic acid.
Insights
Novel azulene-containing retinoids effectively suppressed cancer cell transformation and enhanced communication between cells. Azulene-based retinobenzoic acids, similar to TTNPB, showed greater efficacy than retinoic acid analogs.
Area of Science:
- Medicinal Chemistry
- Cancer Research
- Cell Biology
Background:
- Retinoids are crucial in regulating cell differentiation and proliferation.
- Carcinogen-induced neoplastic transformation is a key process in cancer development.
- Gap junctional communication (GJC) plays a role in preventing cancer progression.
Purpose of the Study:
- To synthesize and evaluate novel azulene-containing retinoids.
- To assess their efficacy in suppressing carcinogen-induced neoplastic transformation.
- To investigate their effect on gap junctional communication and connexin 43 expression.
Main Methods:
- Preparation of two series of azulenic retinoids: retinoic acid analogs and TTNPB analogs.
- In vitro mouse fibroblast C3H/10T1/2 cell bioassay to assess transformation inhibition.
- Evaluation of gap junctional communication and connexin 43 expression in treated cells.
Main Results:
- Two azulenic retinobenzoic acid derivatives (compounds 7 and 11) completely inhibited transformation at 10(-6) M.
- The most active retinoids enhanced gap junctional communication and up-regulated connexin 43 expression.
- Azulenic retinobenzoic acid analogs were generally more effective than retinoic acid analogs.
Conclusions:
- Novel azulene-containing retinoids, particularly azulenic retinobenzoic acids, are potent inhibitors of neoplastic transformation.
- These compounds enhance gap junctional communication, suggesting a mechanism for their anti-cancer activity.
- The structural similarity to TTNPB is important for the observed biological activity.