Selectively Targeting T- and B-Cell Lymphomas: A Benzothiazole Antagonist of α₄β₁ Integrin

Abstract

Current cancer chemotherapeutic agents clinically deployed today are designed to be indiscriminately cytotoxic, however achieving selective targeting of cancer malignancies would allow for improved diagnostic and chemotherapeutic tools. Integrin α4β1, a heterodimeric cell surface receptor, is believed to have a relaxed conformation in normal cells and an active conformation in cancerous cells, specifically T- and B-cell lymphomas. This highly attractive yet poorly understood receptor has been selectively targeted with the bisaryl urea peptidomimetic antagonist 1. However, concerns regarding its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzothiazole moiety, resulting in an analog with improved physicochemical properties, solubility and kidney:tumor ratio while maintaining potency (6; IC50 = 53 pM). The results presented herein utilized heterocyclic and solid-phase chemistry, cell adhesion assay, and in vivo optical imaging using the cyanine dye Cy5.5 conjugate.

Halogenated Benzimidazole Carboxamides Target Integrin α4β1 on T-Cell and B-Cell Lymphomas

“…Compounds 1–2 (as well as 1 -Cy5.5 and 2 -Cy5.5), 9 , 14 , and 15a–b were previously reported (3, 14, 16, 20). The synthesis of 3–6 was analogous to our previous work (16), however the analytical data for these compounds is listed below. The synthesis of 7–8 , 10–13 , and 16–21 is described below.…”

“…Following our procedure for benzimidazole analogues (16) afforded 3 as a white solid (10 mg, 44%): ESI-MS ( m/z ) 798.8 (M+H) + , ESI-HRMS for C 41 H 49 FN 9 O 7 (M+H) + : Calcd, 798.3733; found, 798.4481 ( m/z ). Purity was determined to be 96% as determined by analytical HPLC.…”

“…Our previously reported methods (16) were used with the following exceptions: A sealable microwave tube was used as the reaction vessel and after the consumption of 9 as determined by TLC, 1,3-diisopropylcarbodiimide (451 μL, 2.90 mmol) was added, the tube was sealed, and the reaction mixture was microwave heated to 80 °C for 11 min. After our previously described workup, this crude ester was then dissolved in DMF (8 mL), transferred to a sealable microwave tube, treated with Ba(OH) 2 (1.65 g, 9.65 mmol), and microwave heated to 140 °C for 21 min.…”

“…3 and 15) and the benzothiazole analogue 2 -Cy5.5 (KLCA14-Cy5.5; Fig. 1b; Ref. 16) both showed high affinity and specificity for B- and T-cell lymphomas containing activated α 4 β 1 integrin, with the latter showing improved tumor:kidney signal.…”

“…16) both showed high affinity and specificity for B- and T-cell lymphomas containing activated α 4 β 1 integrin, with the latter showing improved tumor:kidney signal. This is likely due to the improved solubility of 2-arylamino azole heterocycle (14, 16) over the bisaryl urea as these heterocycles have a lower log P , a higher dipole moment, and an increased acidity of the 2-arylamino N-H (p K a = 5.5–6.5; Ref. 19).…”