Synthesis and characterization of selected heteroarotinoids. Pharmacological activity as assessed in vitamin A deficient hamster tracheal organ cultures. Single-crystal x-ray diffraction analysis of 4,4-dimethylthiochroman-6-yl methyl ketone 1,1-dioxide and ethyl (E)-p-[2-(4,4-dimethylthiochroman-6-yl)propenyl]benzoate

Waugh, K. M.; Berlin, K. Darrell; Ford, W. T.; Holt, E. M.; Carrol, J. P.; Schomber, P. R.; Thompson, M. D.; Schiff, Leonard J.

doi:10.1021/jm00379a021

Cited by 42 publications

(27 citation statements)

References 2 publications

(2 reference statements)

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“…[38] Substitution of the C 4 methylene group of aromatic retinoids with heteroatoms leads to a class of retinoids termed heteroarotinoids, which have demonstrated significant potential as anticancer agents due to their activity as inhibitors of the induction of orthinine decarboxylase (ODC) [39] and their resultant ability to prevent or inhibit the transformation of healthy cells into cancerous cells. [40] In addition, several heteroarotinoids exhibit much reduced toxicities, [39a, 40a] in comparison to their carbocyclic analogues, with the reduced toxicity believed to result from the incorporation of the heteroatom.…”

Section: Modification Of the Hydrophobic Unitmentioning

confidence: 99%

Synthetic Retinoids: Structure–Activity Relationships

Barnard

Collings

Whiting

et al. 2009

Chemistry A European J

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Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells.

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Section: Modification Of the Hydrophobic Unitmentioning

confidence: 99%

Synthetic Retinoids: Structure–Activity Relationships

Barnard

Collings

Whiting

et al. 2009

Chemistry A European J

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“…3 Certain heteroarotinoids have demonstrated anticancer activity as well as low toxicity. [4][5][6][7][8] We now report the growth inhibitory activity of a variety of heteroarotinoids 5-19 (Chart 1) against head and neck squamous cell carcinoma (HNSCC) cell lines, SCC-2 and SCC-38. The heteroarotinoids possess a range of flexibility in terms of the linking groups attached to the aryl ring and, in most cases, between two aryl rings.…”

Section: Introductionmentioning

confidence: 99%

Heteroarotinoids Inhibit Head and Neck Cancer Cell Lines in Vitro and in Vivo Through Both RAR and RXR Retinoic Acid Receptors

Zacheis

Dhar

et al. 1999

J. Med. Chem.

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A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10 7 SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-transretinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0.05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARR, RXRR, and RXR were similar in the two cell lines, while RAR expression was higher in SCC-2 over SCC-38, and RARγ expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.

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“…To reduce the toxicity of arotinoids, we incorporated oxygen or sulfur heteroatoms in the cyclic ring of arotinoids. The resulting compounds, called Heteroarotinoids (Hets), exhibited similar biological activities to retinoic acid and arotinoids [42,47], but significantly less toxicity [42,46]. The clinical application of a Het called Tazarotene (produced by Allergan) for treatment of psoriasis, has confirmed the predicted improvement in therapeutic ratio for compounds with heteroatoms [48].…”

Section: Introductionmentioning

confidence: 92%

Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

Naylor¹,

Thompson²,

Lightfoot³

et al. 2013

JCT

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New strategies are needed to treat cancers that do not respond to chemotherapy or resist chemotherapy after responding initially. The objective of this study was to evaluate non-cytotoxic drugs against two of these cancers, melanoma and ovarian cancer. Imiquimod is an immune stimulant that induces apoptosis in cancer cells. Flexible-Heteroarotinoids (Flex-Hets) are small molecules that regulate growth, differentiation and apoptosis in cancer cells with reduced effects on normal cells. Both imiquimod and SHetA2 inhibited growth and induced apoptosis in the B16 melanoma cell line and cisplatin-sensitive A2780 and cisplatin-resistant OVCAR-3 ovarian cancer cell lines. The growth inhibition was additive in A2780 and B16, and synergistic in OVCAR-3. Both compounds inhibited endothelial tube branching in vitro and exerted an additive effect when combined. Various combinations of imiquimod and SHetA2 did not cause significant differences in the overall survival in the syngeneic B16 murine melanoma model. SHetA2 induced complete tumor regression and a melanoma-free natural life-span in two mice. These cures occurred in one of ten mice treated with oral SHetA2 and one of ten mice intratumorally-injected with SHetA2. Exploratory modeling of the distribution of survival times suggested that the two surviving mice represent rare events. Histologic evaluation of the tumors revealed that imiquimod induced necrosis, SHetA2 induced differentiated architecture and increased cytoplasm, both agents reduced mitotic indices and angiogenesis and neither agent counteracted the effects of the other. No overt toxicities were observed. In conclusion, imiquimod and SHetA2 exhibit complementary anti-cancer activity in vitro and SHetA2 has promise as a single agent.

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Cited by 42 publications

References 2 publications

Synthetic Retinoids: Structure–Activity Relationships

Synthetic Retinoids: Structure–Activity Relationships

Heteroarotinoids Inhibit Head and Neck Cancer Cell Lines in Vitro and in Vivo Through Both RAR and RXR Retinoic Acid Receptors

Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

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