Biological Evaluation of 2-Aryl-2-fluoropropionic Acids as Possible Platforms for New Medicinal Agents

Abstract

We have been studying the design, synthesis, and biological evaluation of chiral fluorine-containing organic compounds as effective analogues of pharmaceutically important molecules. Introduction of fluorine into a prototype molecule results in minimal steric alterations, which can facilitate interactions of fluorinated biomolecules or medicinals with enzyme active sites, receptor recognition sites, transport mechanisms, and other biological systems.1) On the other hand, the presence of fluorine can alter the biological consequences of these interactions, often in a useful way. As a part of our research, we recently reported the synthesis of optically active 2-aryl-2-fluoropropionic acids 1, which possess a unique structure with the fluorine atom located at the stereogenic center (Fig. 1).2)The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and COX-2 activities. An increasing number of epidemiological, clinical, and laboratory studies have suggested that NSAIDs, including the series of 2-arylpropionic acids 2 (Fig. 2), may also be able to inhibit the initiation and proliferation of some tumors. [3][4][5] For the following reasons we thought that the fluorinated analogues of 2 could be possible platforms for multi-dimensional, clinically effective therapeutic agents. First, there have been reported a few potent leads having a chiral fluorine-containing structure, such as fluorothalidomide, fluorodonepezil, etc.6-9) These compounds were found to be pharmacologically more effective than the fluorine-free parent compounds. This suggests that the screening of biological activities of chiral fluorine-containing acids 1 could guide the development of new kinds of medicinal agents. Secondly, there have been literature reports describing an in vivo inversion of less active (R)-enantiomer into more active (S)-enantiomer in some 2-arylpropionic acids 2 (Fig. 2). [10][11][12][13] Such in vivo epimerization of chiral medicinal agents is quite rare although there are several examples of in vivo racemization. It is apparent that nonepimerizable 2-aryl-2-fluoropropionic acids 1 could serve as useful tools to clarify the roles of stereochemical lability in living organisms.To examine the pharmacological potential of chiral 2-aryl-2-fluoropropionic acids 1 as pharmacological leads, we have evaluated them with respect to both COX inhibitory activities and antiproliferative activities of cancer cell lines. In this paper, we present the results of this biological evaluation and discuss the results in terms of the potential for further drug development. Results and DiscussionWe first investigated the inhibitory activity of the racemic and optically active fluorinated acids 1a-e toward COX-1 and COX-2. The corresponding non-fluorinated racemates 2a-e, indomethacin, and NS-398 were also investigated for reference. Their inhibitory activities are shown in Table 1.The inhibitory activities of (Ϯ)-1c and (Ϯ)-1e toward COX-1 were much lower than those of the corresponding acids (Ϯ)-2c and (Ϯ)-2e, while the activity of (Ϯ)-1c ...

Ibuprofen and Lipoic Acid Diamides as Potential Codrugs with Neuroprotective Activity

“…Ibuprofen methylester 4 was synthesized as previously reported [29]. Compounds 1-3 were synthesized as outlined in Scheme 1.…”

Electrochemical Carboxylation of α,α-Difluorotoluene Derivatives and Its Application to the Synthesis of α-Fluorinated Nonsteroidal Anti-Inflammatory Drugs

“…There are several reports on synthesis of a-fluo-rinated NSAIDs [17][18][19][20][21][22] and their biological evaluation. 23 Most of the reported synthesis involves fluorination of esters or derivatives of NSAIDs, 17,[19][20][21][22] and intractable and/ or hazardous reagents, such as diethylaminosulfur trifluoride (DAST), 17,22 perchloryl fluoride (FClO 3 ), 19 and acetyl hypofluorite (AcOF), 21 were used as a fluorinating reagent. By using the present EC of a,a-difluoroethylarenes, synthesis of a-fluorinated NSAIDs could be achieved under neutral and mild conditions without such reagents.…”

Design, Synthesis, and Biological Evaluation of New Peptide Analogues as Selective COX‐2 Inhibitors

“…The data of COX‐1/COX‐2 inhibition assay are mentioned in Table . SAR data (IC 50 values) acquired by the calculation of the in vitro potency of the heading compounds to inhibit the COX‐1 and COX‐2 isozymes displayed that the most peptides ( 1a–7b ) were acceptable inhibitors of the COX‐2 isozyme with IC 50 values in the 0.06–0.44 µM range, and COX‐2 selectivity indices in the 84.3–>500 range . Our results showed that the COX inhibition from the points of potency and selectivity was affected by the nature of amino acid substituents and SO 2 Me or N 3 pharmacophore at the para position of the end phenyl ring.…”

“…The ability of the synthesized compounds to inhibit ovine COX‐1 and COX‐2 (IC 50 value, μM) was determined using chemiluminescent enzyme assays kit (Cayman Chemical, Ann Arbor, MI, USA) according to the previously reported method .…”