We have developed a modular scaffold for preparing high-affinity, homo-multivalent inhibitors of the prostate-specific membrane antigen (PSMA) for imaging and therapy of prostate cancer (PCa). Our system contains a lysine-based (∝-, ε-) dialkyne residue for incorporating a PSMA binding Lys-Glu urea motif exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety. The utility of the multivalent scaffold was examined by synthesizing bivalent compounds 2 and 3 and comparing them with the monovalent analog 1. Determination of inhibition constants (Ki) revealed that bivalent 2 (0.2 nM) and 3 (0.08 nM) are significantly more potent (~ 5 fold and ~ 11 fold, respectively) inhibitors of PSMA than monovalent 1 (0.9 nM). A single photon emission computed tomography (SPECT)-CT imaging study of [111In]3 demonstrated high and specific uptake in PSMA+ PC-3 PIP tumor until at least 48 h post-injection, with rapid clearance from non-target tissues, including kidney. A biodistribution study revealed that [111In]3 demonstrated 34.0 ± 7.5 percent injected dose per gram of tissue in PSMA+ tumor at 24 h post-injection and was capable of generating target-to-non-target ratios of ~ 379 in PSMA+ PC-3 PIP tumors vs. isogenic PSMA-negative PC3-flu tumors in vivo. The click chemistry approach affords a convenient strategy toward multivalent PSMA inhibitors of enhanced affinity and superior pharmacokinetics for imaging.
The marine-derived macrolides latrunculins A (1) and B, from the Red Sea sponge Negombata magnifica, have been found to reversibly bind actin monomers, forming a 1:1 complex with G-actin and disrupting its polymerization. The microfilament protein actin is responsible for several essential functions within the cell such as cytokinesis and cell migration. One of the main binding pharmacophores of 1 to G-actin was identified as the C-17 lactol hydroxyl moiety that binds arginine 210 NH. Latrunculin A-17-O-carbamates 2-6 were prepared by reaction with the corresponding isocyanates. Latrunculin A (1) and carbamates 4-6 displayed potent anti-invasive activity against the human highly metastatic human prostate cancer PC-3M cells in a Matrigel™ assay at a concentration range of 50 nM-1 µM. Latrunculin A (1, 500 nM) decreased the disaggregation and cell migration of PC-3M-CT+ spheroids by three-fold. Carbamates 4 and 5 were two and half and five-fold more active than 1, respectively, in this assay with less actin binding affinity. Latrunculin A (1, IC 50 6.7 µM) and its 17-O-[N-(benzyl)carbamate (6, IC 50 29 µM) suppress hypoxia-induced HIF-1 activation in T47D breast tumor cells.Latrunculin A (1) and B are macrolides reported by Kashman and coworkers from the Red Sea sponge Negombata magnifica Kelly-Borges and Vacelet (Podospongiidae). 1 Latrunculins are reported to decrease intraocular pressure and increase outflow facility without corneal effects in monkeys.2 , 3 Latrunculin B and analogs showed antiangiogenic, antimetastatic, and antimicrobial activities.4 The most important biological effects of latrunculins are their abilities to disrupt microfilament organization and inhibit microfilament-mediated processes without affecting the organization of the microtubular system. 5 The latrunculins bind reversibly to the cytoskeleton actin monomers, forming 1:1 complexes with G-actin and disrupting polymerization. 5 Actin-active agents are attracting more attention in the field of cancer chemotherapy because microfilament and microtubule proteins form versatile dynamic polymers that can define cell polarity, organize cytoplasmic organelles, control cell shape and promote stable cell-cell and cell-matrix adhesions, and generate protrusive forces required for migration. 6-8 These functions usually fail and become abnormal in cancer cells. 6 Based on X-ray crystallography, the binding site of 1 has been located between subdomains II and IV, in the vicinity of the ATP binding cleft of the protein target in the actin monomer. 9, 10 The binding pharmacophores of 1 to G-actin were identified as follows: C-1 carbonyl oxygen through water to glutamate 214 carboxy, C-17 lactol hydroxyl to arginine 210 NH (major binding), C-17 pyran oxygen to tyrosine 69 hydroxy, thiazolidinone NH to aspartate 157 carboxy, and thiazolidinone C-20 carbonyl oxygen to threonine 186 hydroxy. 9, 10 Only the thiazolidinone NH group acts as a hydrogen bonding donor while the rest of the binding functions act as hydrogen bonding acceptors.9 , 10Semi-s...
Differential expression of surface proteins on normal vs malignant cells provides the rationale for the development of receptor-, antigen-, and transporter-based, cancer-selective imaging and therapeutic agents. However, tumors are heterogeneous, and do not always express what can be considered reliable, tumor-selective markers. That suggests development of more flexible targeting platforms that incorporate multiple moieties enabling concurrent targeting to a variety of putative markers. We report the synthesis, biochemical, in vitro, and preliminary in vivo evaluation of a new heterobivalent (HtBv) imaging agent targeting both the prostate-specific membrane antigen (PSMA) and integrin-αvβ3 surface markers, each of which can be overexpressed in certain tumor epithelium and/or neovasculature. The HtBv agent was functionalized with either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or the commercially available IRDye800CW. DOTA-conjugated HtBv probe 9 bound to PSMA or αvβ3 with affinities similar to those of monovalent (Mnv) compounds designed to bind to their targets independently. In situ energy minimization experiments support a model describing the conformations adapted by 9 that enable it to bind both targets. IRDye800-conjugated HtBv probe 10 demonstrated target-specific binding to either PSMA or integrin-αvβ3 overexpressing xenografts. HtBv agents 9 and 10 may enable dual-targeted imaging of malignant cells and tissues in an effort to address heterogeneity that confounds many cancer-targeted imaging agents.
Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four 18F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[18F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [18F]23 and 4-iodo-2-[18F]fluorobenzoyllysine OPA carbamate [18F]24 in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [18F] 23 is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [18F]24, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues.
The CXCR4 chemokine receptor is integral to several biological functions and plays a pivotal role in the pathophysiology of many diseases. As such, CXCR4 is an enticing target for the development of imaging and therapeutic agents. Here we report the evaluation of the POL3026 peptidomimetic template for the development of imaging agents that target CXCR4. Structural and conformational analyses of POL3026 and two of its conjugates, DOTA (POL-D) and PEG12-DOTA (POL-PD), by circular dichroism, two-dimensional NMR spectroscopy and molecular dynamics calculations are reported. In silico observations were experimentally verified with in vitro affinity assays and rationalized using crystal structure-based molecular modeling studies. [111In]-labeled DOTA conjugates were assessed in vivo for target specificity in CXCR4 expressing subcutaneous U87 tumors (U87-stb-CXCR4) through single photon emission computed tomography (SPECT/CT) imaging and biodistribution studies. In silico and in vitro studies show that POL3026 and its conjugates demonstrate similar interactions with different micelles that mimic cellular membrane and that the ε-NH2 of lysine7 is critical to maintain high affinity to CXCR4. Modification of this group with DOTA or PEG12-DOTA led to the decrease of IC50 value from 0.087 nM for POL3026 to 0.47 nM and 1.42 nM for POL-D and POL-PD, respectively. In spite of the decreased affinity toward CXCR4, [111In]POL-D and [111In]POL-PD demonstrated high and significant uptake in U87-stb-CXCR4 tumors compared to the control U87 tumors at 90 min and 24 h post injection. Uptake in U87-stb-CXCR4 tumors could be blocked by unlabeled POL3026, indicating specificity of the agents in vivo. These results suggest POL3026 as a promising template to develop new imaging agents that target CXCR4.
A series of aroyl derivatives of 4-(2-chloroethyl)semicarbazide were designed and synthesized to explore their antiproliferative activity against human brain carcinoma (U251) and human liver carcinoma (Hepg2) cell lines. The synthesized compounds were characterized by elemental analyses and spectroscopic data. It was established that compounds in which semicarbazide fragments are substituted with a (2-indolyl)carbonyl moiety showed a higher cytotoxic activity than the corresponding benzoyl derivatives. 1-[(5-Benzyloxy-1H-indol-2-yl)carbonyl]-4-(2-chloroethyl)semicarbazide (24) showed the highest cytotoxic activity against Hepg2 (IC 50 = 21 mg/ml), while 4-(2-chloroethyl)-1-[(5-methoxy-1H-indol-2-yl)carbonyl]semicarbazide (23) was the most active compound against U251 (IC 50 = 8 mg/ml).
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