Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs.

Makaluvamine J, a pyrroloiminoquinone alkaloid of marine sponge origin, and its analogs were synthesized and assessed for their potential to develop as a novel and selective growth inhibitor targeting human pancreatic cancer PANC-1 cells. Ts-damirone B, a common precursor featuring a pyrroloiminoquinone core structure, was synthesized through Bartoli indole synthesis and IBX-mediated oxidation. Late-stage diversification at N-5 and N-9 yielded makaluvamine J and several analogs. A structure-activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at N-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at N-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog 24 showed potent and selective cytotoxicity (IC50 = 0.029 µM, selective index = 13.1), exceeding those of natural products.

Feasibility of using a 99mTc-hydroxamamide complex containing an albumin binder moiety for in vivo albumin labeling-based tumor imaging.

Human serum albumin (HSA), which is distributed throughout the blood, is used as a carrier for transporting drugs to tumors based on the enhanced permeability and retention (EPR) effect. To develop an agent for the in vivo radiolabeling of endogenous albumin, we designed and synthesized novel hydroxamamide (Ham)-based technetium-99m (99mTc) complexes, which contained a monovalent or bivalent 4-(4-iodophenyl)butyric acid (IA) derivative as an albumin binder (ALB) moiety ([99mTc]AB2 and [99mTc]ALB2, respectively), and evaluated their utility for in vivo tumor imaging. In an in vitro HSA-binding assay, [99mTc]AB2 and [99mTc]ALB2 showed greater binding to HSA than [99mTc]BHam, a 99mTc-Ham complex without an ALB moiety. In an in vivo biodistribution assay, [99mTc]ALB2 showed marked blood and tumor retention (25.13 and 4.61% injected dose (ID)/g, respectively, at 1 h postinjection), suggesting that the EPR effect had been induced. However, [99mTc]AB2 showed no marked blood or tumor retention (4.16 and 0.75% ID/g, respectively, at 1 h postinjection), probably because the affinity of the monovalent IA derivative for albumin was insufficient to induce the EPR effect. These findings indicated that the multivalent interactions of [99mTc]ALB2 had enhanced its affinity for albumin. 99mTc-complexes containing multivalent ALB moieties may be useful for tumor imaging.

Synthesis and evaluation of novel technetium-99m-hydroxamamide complex based on imidazothiadiazole sulfonamide targeting carbonic anhydrase-IX for tumor imaging.

Carbonic anhydrase-IX (CA-IX) is an attractive target for detecting tumors associated with a poor prognosis. We previously reported a [99mTc]hydroxamamide complex based on ureidosulfonamide as a CA-IX ligand ([99mTc]URB2A), which showed a favorable affinity for CA-IX high-expressing cells in vitro and tumors in vivo; however, radioactivity retention in the blood pool suggested a high background signal on imaging. To improve the pharmacokinetics of [99mTc]URB2A, in this study, we designed and synthesized [99mTc]ISB2 based on imidazothiadiazole sulfonamide, which exhibited greater CA-IX affinity and faster clearance from the blood pool than ureidosulfonamide in studies using corresponding 111In-labeled compounds, and evaluated its utility for CA-IX imaging. In an in vitro cell binding assay, [99mTc]ISB2 markedly bound to CA-IX high-expressing (HT-29) cells; moreover, its binding was greater than that of [99mTc]URB2A. In an in vivo biodistribution assay, [99mTc]ISB2 showed faster clearance from the blood pool than [99mTc]URB2A; however, lower HT-29 tumor accumulation was observed. Further structural modification of [99mTc]ISB2 to improve its stability may lead to the development of a useful [99mTc]hydroxamamide complex for CA-IX imaging.