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[Studies on retinoids. IV. Design, synthesis and structure-activity relationships of di-t-butylphenyl compounds]
1Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050.
Abstract:
Retinoic acid and its analogues play important roles in modulating cell growth, differentiation, immunity and apoptosis. Clinically they are used for cancer chemoprevention and chemotherapy. Based upon the moiety of 3,5-di-t-butyl-4-hydroxy phenyl ring, a series of substituted aromatic amide, ester and chalcones were designed and synthesized, which mimic the molecular shape, size, and spacial disposition of functional groups of retinoic acid. The general structure is as follows: [formula: see text] where R stands for hydrogen atom or methyl group, Y is the linkage -CONH-, -NHCO-, -COO-, -COCH = CH-, or a member of a heterocycle, X represents various substituents at different positions. The SAR indicates that the presence of hydrophobic group(s) at one end of the molecule, and a carboxyl group at the other end, and a conjugative system of molecule are necessary and full prerequisite for exhibiting activity. Loss of any one factor of them will abolish the activity. Being obligatory for anti-oxidative effect, the phenolic hydroxy group does not convey biological activity, because after methylation of the hydroxy group the compound increases the differentiation-inducing activity and loses the anti-oxidative effect, indicating that there is no correlation between the two activities. With a stable conformation of two phenyl rings with cis-conformation N-methylated acyl amide (No. 30) features in bent shape of the molecule, instead of an extended conformer, which is taken by the non-N-methylated partner and all-trans retinoic acid. A bent conformer of No. 30 accounts for the inactivity. In this paper compounds No. 4f, 4g, 5a, 7, 13, 32, 37, and 38 exhibited significant activity among them 4-[3-(3, 5-di-t-4-methoxyphenyl)-3-oxo-1-propenyl] benzoic acid (No. 38) showed high activity comparable to that of retinoic acid. The pharmacological action of No. 38 is under investigation.
Insights
Researchers synthesized novel compounds mimicking retinoic acid (RA) for cancer therapy. Compound 38 demonstrated high activity, comparable to RA, highlighting its potential in cancer chemoprevention and chemotherapy.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Pharmacology
Context:
- Retinoic acid (RA) and its analogs are crucial in regulating cell processes and are used clinically for cancer treatment.
- Designing novel compounds that mimic RA's structure is a key strategy in developing new cancer therapies.
Purpose:
- To design and synthesize novel aromatic amides, esters, and chalcones that structurally mimic retinoic acid.
- To evaluate the structure-activity relationship (SAR) of these synthesized compounds for their biological activity.
- To identify potent compounds for potential use in cancer chemoprevention and chemotherapy.
Summary:
- A series of compounds were synthesized based on the 3,5-di-t-butyl-4-hydroxy phenyl moiety to mimic retinoic acid.
- Key structural features for activity include hydrophobic groups, a carboxyl group, and a conjugated system.
- Compound 38, 4-[3-(3,5-di-t-4-methoxyphenyl)-3-oxo-1-propenyl] benzoic acid, exhibited significant activity comparable to retinoic acid.
Impact:
- Identified essential structural requirements for retinoic acid-like activity, guiding future drug design.
- Discovered compound 38 as a promising candidate for further investigation in cancer treatment.
- Demonstrated that anti-oxidative effects are not correlated with differentiation-inducing activity in these compounds.