The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

https://www.tandfonline.com/doi/pdf/10.1080/14756360701425014

The role of fluorine in medicinal chemistry

A series of water-soluble L-lysyl- and L-alanyl-amide prodrugs of the lipophilic antitumor 2-(4-aminophenyl)benzothiazoles has been synthesized to address formulation and bioavailability issues related to the desired parenteral administration of the chosen clinical candidate. The prodrugs exhibit the required pharmaceutical properties of good water solubility (in weak acid) and stability at ambient temperature and degradation to free base in vivo. The lysyl-amide of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (NSC 710305, 6d) has been selected for phase 1 clinical evaluation.

Antitumor benzothiazoles. 16. Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid prodrugs.

A new, convenient method for the syntheses of 2-substituted benzimidazole and benzothizole is described. Short reaction times, large-scale synthesis, easy and quick isolation of the products, excellent chemoselectivity, and excellent yields are the main advantages of this procedure.

Mild and Highly Efficient Method for the Synthesis of 2-Arylbenzimidazoles and 2-Arylbenzothiazoles

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substituted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioisomeric 5- and 7-fluoro-benzothiazoles were formed from the established Jacobsen cyclization of precursor 3-fluoro-thiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these target compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently cytotoxic (GI50 10 ?M) against PC 3 prostate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dose?response relationship characteristically shown by the benzothiazole series against sensitive cell lines was exhibited by the 4- and 6-fluoro-benzothiazoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The most potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h) which, unlike the 6-fluoro isomer (10d), produces no exportable metabolites in the presence of sensitive MCF-7 cells. Induction of cytochrome P450 CYP1A1, a crucial event in determining the antitumor specificity of this series of benzothiazoles, was not compromised. 10h is currently the focus of pharmaceutical and preclinical development.

Antitumor benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles.

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry.

2-(4-Aminophenyl)benzothiazoles 1 and their N-acetylated forms have been converted to C- and N-hydroxylated derivatives to investigate the role of metabolic oxidation in the mode of action of this series of compounds 2-(4-Amino-3-methylphenyl)benzothiazole (1a, DF 203, NSC 674495) is a novel and potent antitumor agent with selective growth inhibitory properties against human cancer cell lines Very low IC(50) values (<01 microM) were encountered in the most sensitive breast cancer cell lines, MCF-7 and T-47D, whereas renal cell line TK-10 was weakly inhibited by 1a Cell lines from the same tissue origin, MDA-MB-435 (breast), CAKI-1 (renal), and A498 (renal), were insensitive to 1a Accumulation and metabolism of 1a were observed in sensitive cell lines only, with the highest rate of metabolism occurring in the most sensitive MCF-7 and T-47D cells Thus, differential uptake and metabolism of 1a by cancer cell lines may underlie its selective profile of anticancer activity A major metabolite in these sensitive cell lines has been identified as 2-(4-amino-3-methylphenyl)-6-hydroxybenzothiazole (6c) Hydroxylation of 1a was not detected in the homogenate of previously untreated MCF-7, T-47D, and TK-10 cells but was readily observed in homogenates of sensitive cells that were pretreated with 1a Accumulation and covalent binding of [(14)C]1a derived radioactivity was observed in the sensitive MCF-7 cell line but not in the insensitive MDA-MB-435 cell line The mechanism of growth inhibition by 1a, which is unknown, may be dependent on the differential metabolism of the drug to an activated form by sensitive cell lines only and its covalent binding to an intracellular protein However, the 6-hydroxy derivative 6c is not the 'active' metabolite since, like all other C- and N-hydroxylated benzothiazoles examined in this study, it is devoid of antitumor properties in vitro

Antitumor benzothiazoles. 8. Synthesis, metabolic formation, and biological properties of the C- and N-oxidation products of antitumor 2-(4-aminophenyl)benzothiazoles.

Eiji Kashiyama

Papers

Antitumor benzothiazoles. 8. Synthesis, metabolic formation, and biological properties of the C- and N-oxidation products of antitumor 2-(4-aminophenyl)benzothiazoles.