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. 2010 Jul 1;70(13):5448-56.
doi: 10.1158/0008-5472.CAN-09-3736. Epub 2010 Jun 8.

Halogenated benzimidazole carboxamides target integrin alpha4beta1 on T-cell and B-cell lymphomas

Richard D Carpenter  1 , Arutselvan Natarajan, Edmond Y Lau, Mirela Andrei, Danielle M Solano, Felice C Lightstone, Sally J Denardo, Kit S Lam, Mark J Kurth
Affiliations

Halogenated benzimidazole carboxamides target integrin alpha4beta1 on T-cell and B-cell lymphomas

Richard D Carpenter et al. Cancer Res. .

Abstract

Integrin alpha(4)beta(1) is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin alpha(4)beta(1) antagonists. We documented tumor uptake of derivatives labeled with (125)I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin alpha(4)beta(1) predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic ((18)F) or radiotherapeutic ((131)I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies.

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Figures

Figure 1
Figure 1
Structures of: (a) 1-Cy5.5 (Ref. 3), (b) 2-Cy5.5 (Ref. 16), (c) halobenzimidazole analogues 3–7, and (d) the bishalo analogue 8 and 18 which incorporate the bromobenzimidazole moiety and a distal radioiodide.
Figure 2
Figure 2
(a) Potency (IC50), estimated binding energies, calculated interaction energies, and amide-halogen geometries, where the amide represents a nearby primary amide of Asn161 (α4 subunit) side chain: a. see Ref. 14 for more on 15a, Ref. 16 for more on 15b; b. Energies are expressed in units of kcal/mol; c. estimated binding energies (Ebind), where Ebind = RT*ln[IC50(X = halogen)/IC50(X = H)]; d. Calculated interaction energy for amide-halogen interaction (gas-phase) using MP2/6-311++G(d,p)//B3LYP/6-311++G(d,p) level of theory, second values are the BSSE corrected energies; e. Distances for the van der Waal's (vdW) radii of each halogen are expressed in Å; f. Distances (in Å) represent the C(O)NRH---XAr H-bond length; g. Represents the H-X-Ar angle in the C(O)NRH---XAr H-bond. (b) Electrostatic potential maps for 3–6 and 15a–b.
Figure 3
Figure 3
Preparation of 18 from the tyrosine derivative 19.
Figure 4
Figure 4
Ex vivo radio-uptake data of 18 for various tumors and organs.
See this image and copyright information in PMC

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