Chondromodulating chimeric prodrugs of diacetylrhein: synthesis and evaluation in monoiodoacetate-induced hyperalgesia.

Abstract

Chondromodulating chimeric prodrugs of diacetylrhein were synthesized with an objective of potentiating its moderate anti-inflammatory effect and optimizing its hydrophilic/lipophilic balance by conjugating it with essential amino acids through a bioreversible amide linkage. In vitro release in HCl buffer (pH 1.2) showed insignificant release of diacetylrhein. However in phosphate buffer (pH 7.4), almost complete release of diacetylrhein was attained over a period of 4.5 h, following first order kinetics. The prodrug was screened extensively for therapeutic efficacy in monoiodoacetate induced rat hyperalgesia model for levels of various markers of osteoarthritis, knee diameter and locomotor activity over a period of three months. Amongst the three prodrugs synthesized, diacetylrhein-L-tryptophan prodrug exhibited highest activity by reducing knee diameter, serum alkaline phosphatase and serum glucosaminoglycan to the baseline levels while increasing the spontaneous locomotor activity. It was found to provide maximum protection against Freund's adjuvant arthritis with minimum ulcerogenic potential and better chondroprotection than diacetylrhein.

• Authors: Suneela Dhaneshwar, Dipmala Patil
• Journal: Medicinal chemistry (Shariqah (United Arab Emirates)) (Med Chem) Vol. 9 Issue 3 Pg. 449-58 (May 2013) ISSN: 1875-6638 [Electronic] Netherlands
• PMID: 22920092 (Publication Type: Journal Article)

Chemical References

• Anthraquinones
• Prodrugs
• diacerein
• Iodoacetic Acid

Topics

• Animals
• Anthraquinones (chemical synthesis, chemistry, therapeutic use)
• Chondrocytes (pathology)
• Disease Models, Animal
• Hyperalgesia (chemically induced, drug therapy)
• Iodoacetic Acid
• Osteoarthritis (pathology)
• Prodrugs (chemical synthesis, chemistry, therapeutic use)
• Rats