3-Methylbutanoic acid

Methyl 2-(2-[18F]fluoro-4-nitrobenzamido)-3- methylbutanoic acid

The most commonly used radiochemical for positron emission tomography (PET) imaging of brain or systemic cancerous tumors is 2-[18F]fluorodeoxyglucose ([18F]FDG), a radiotracer approved by the United States Food and Drug Administration for imaging purposes, but the use of this radiolabel is not without limitations because, among several application drawbacks, it tends to produce a high background in the brain and inflamed tissues during imaging (1, 2). To circumvent problems encountered with [18F]FDG, some investigators developed and evaluated unnatural amino acid (aa) derivatives such as O-2-[18F]fluoroethyl-L-tyrosine (L-[18F]FET) for the detection of tumors, particularly of the brain, and it was shown that L-[18F]FET was superior to [18F]FDG in distinguishing tumors from inflammation (3). However, the synthesis of 18F-labeled aa is cumbersome and, because an electrophilic substitution reaction is used to introduce the label into the aa, the final labeled product yields are very low (2). An alternative synthetic method of placing a fluoroalkyl group on the aromatic ring of tyrosine was observed to improve the yield of L-[18F]FET, but it prolonged the synthesis time for the radiochemical (4, 5). In an effort to simplify the synthesis of 18F-radiolabeled aas, 18F-labeled fluoroarylvaline derivatives of L-valine were prepared after modifying the aa with 2,4-dinitrobenzoic acid (2). According to the investigators, introduction of 18F at the ortho-position of 2,4-dinitrobenzoic acid is very easy, and the attachment of this moiety to L-valine results in an improved lipophilicity of the molecule. Using this method, two derivatives of L-valine were produced: methyl 2-(2-[18F]fluoro-4-nitrobenzamido)-3-methylbutanoate ([18F]MFNBMB; [18F]1) and methyl 2-(2-[18F]fluoro-4-nitrobenzamido)-3-methylbutanoic acid ([18F]FNBMBA; [18F]2) (2). These radiotracers were evaluated under in vivo conditions, and their biological properties were compared with those of [18F]FDG and L-[18F]FET. This chapter describes the characteristics of [18F]FNBMBA and its biodistribution in tumor-bearing mice. The characteristics of [18F]MFNBMB and its biodistribution in tumor-bearing mice is described in a separate chapter of MICAD (6).

2-{5-[( Z,2 Z)-2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}-3-methylbutanoic Acid as a Potential Anti-Breast Cancer Molecule

It was established that the synthesis of hybrid molecules containing a thiazolidinone and a (2Z)-2-chloro-3-(4-nitrophenyl)prop-2-ene structural fragments is an effective approach for the design of potential anticancer agents. Given the results of the previous SAR-analysis, the aim of the study was to synthesize a novel 4-thiazolidinone derivative Les-3331 and investigate its molecular mechanism of action in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic properties and antiproliferative potential of Les-3331 were determined. The effect of the tested compound on apoptosis induction and mitochondrial membrane potential was checked by flow cytometry. ELISA was used to determine caspase-8 and caspase-9, LC3A, LC3B, Beclin-1, and topoisomerase II concentration. Additionally, PAMPA, in silico or in vitro prediction of metabolism, CYP3A4/2D6 inhibition, and an Ames test were performed. Les-3331 possesses high cytotoxic and antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cells. Its molecular mechanism of action is associated with apoptosis induction, decreased mitochondrial membrane potential, and increased caspase-9 and caspase-8 concentrations. Les-3331 decreased LC3A, LC3B, and Beclin-1 concentration in tested cell lines. Topoisomerase II concentration was also lowered. The most probable metabolic pathways and no DDIs risk of Les-3331 were confirmed in in vitro assays. Our studies confirmed that a novel 4-thiazolidinone derivative represents promising anti-breast cancer activity.

Methyl 2-(2-[18F]fluoro-4-nitrobenzamido)-3-methylbutanoate

The most commonly used radiochemical for positron emission tomography (PET) imaging of brain or systemic cancerous tumors is 2-[¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), a United States Food and Drug Administration approved imaging agent, but the use of this radiolabel is not without limitations because, among several application drawbacks, it tends to produce a high background in the brain and inflamed tissues during imaging (1, 2). To circumvent problems encountered with [¹⁸F]FDG, some investigators developed and evaluated unnatural amino acid (aa) derivatives such as O-2-[¹⁸F]fluoroethyl-L-tyrosine (L-[¹⁸F]FET) for the detection of tumors, particularly of the brain, and it was shown that L-[¹⁸F]FET was superior to [¹⁸F]FDG in distinguishing tumors from inflammation (3). However, the synthesis of ¹⁸F-labeled aa is cumbersome and, because an electrophilic substitution reaction is used to introduce the label into the aa, the final labeled product yields are very low (2). An alternative synthetic method of placing a fluoroalkyl group on the aromatic ring of tyrosine was observed to improve the yield of L-[¹⁸F]FET, but it prolonged the synthesis time for the radiochemical (4, 5). In an effort to simplify the synthesis of ¹⁸F-radiolabeled aas, ¹⁸F-labeled fluoroarylvaline derivatives of L-valine were prepared after modifying the aa with 2,4-dinitrobenzoic acid (2). According to the investigators, introduction of ¹⁸F at the ortho-position of 2,4-dinitrobenzoic acid is very easy, and the attachment of this moiety to L-valine results in an improved lipophilicity of the molecule. Using this method, two derivatives of L-valine were produced: methyl 2-(2-[¹⁸F]fluoro-4-nitrobenzamido)-3-methylbutanoate ([¹⁸F]MFNBMB; [¹⁸F]1) and methyl 2-(2-[¹⁸F]fluoro-4-nitrobenzamido)-3-methylbutanoic acid ([¹⁸F]FNBMBA; [¹⁸F]2) (2). These radiotracers were evaluated under in vivo conditions, and their biological properties were compared with those of [¹⁸F]FDG and L-[¹⁸F]FET. This chapter describes the characteristics of [¹⁸F]MFNBMB and its biodistribution in tumor-bearing mice. The characteristics of [¹⁸F]FNBMBA and its biodistribution in tumor-bearing mice is described in a separate chapter of MICAD (6).

A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408)

Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.