Current Medicinal Chemistry (v.19, #20)

Due to the growing toolkit of targeted contrast agents, molecular imaging continues to play a prominent role in the clinical care of cancer. Peptide-based imaging approaches are of particular significance due to their favorable pharmacokinetic properties, established manufacturing infrastructure, and documented clinical success in whole-body imaging. A logical extension of molecular imaging with peptides is to improve surgical outcomes in cancer through highly sensitive and specific probes which can be used intraoperatively. Advances in fluorescent imaging have resulted in various peptide labeling strategies with intraoperative indications. In this review, we focused on the evolving design of peptide imaging agents starting with the clinically used somatostatin targeting peptides. We then review the current synthetic approaches used for dual-labeled agent development and offer perspectives on optimal protection schemes that can be used for multimodal probe development.

Understanding the expression of tumor specific receptors is important not only for tumor diagnosis but also for planning the strategy for patient treatment. Tumor receptor has been one of the most critical targets for treatment in cancer such as breast, prostate and thyroid cancers. Positron emission tomography (PET) is a part of molecular imaging techniques based on detecting the radiopharmaceuticals that can capture functional or phenotypic changes associated with pathology. The advantages of detecting tumor specific receptors by PET are its non-invasiveness, providing comprehensive information about receptor expression, avoiding the sampling errors, selecting strategy for the treatment of patients and monitoring tumor response to therapy. Hormonal therapy plays a major role in cancer treatment. Therefore, we review the PET radiopharmaceuticals for sex steroid hormone receptor imaging in this article.

Amino acids are required for sustenance of continuous uncontrolled growth of tumor cells, and upregulation of amino acid transporter expression has often been observed in tumor cells to facilitate their accelerated rates of amino acid uptake. Therefore, amino acid transporters have promise as ideal targets for tumor imaging. In fact, many natural and artificial amino acids have been radiolabeled for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging of tumor. In this article, we review the classification, molecular biology, and pharmacological relevance of amino acid transport systems. In addition, we discuss the chemistry, radiochemistry, current clinical applications, and future prospects for the use of radiolabeled amino acid-based probes for PET and SPECT imaging in oncology for each category of radionuclide.

Hypoxia has been observed in a variety of human tumor types and evaluating tumor hypoxia is important because it increases resistance to radiotherapy and chemotherapy by inducing proteomic change that allow the tumor cell to survive in their hypoxic environment. One of the major proteomic changes is HIF-1 expression, and HIF-1 has become a target for anti-cancer drugs development because of its central role in hypoxia-mediated aggressiveness of tumor cells and their resistance to therapy. Since tumor hypoxia is a key mechanism that leads to resistance of treatment, a large number of challenges for hypoxia imaging including magnetic resonance, optical, and nuclear imaging have been reported. These hypoxia imaging techniques may have potential in selecting cancer patients who would benefit from treatments that overcome the presence of hypoxia. Hypoxia imaging could also be used to document whether or not and the extent to which reoxygenation of tumors occurs during cancer treatment. One of key requirements of ideal method for imaging hypoxia is that the method should be non-invasive. From an imaging perspective, PET is also one of leading tools for imaging hypoxia because of its high spatial resolution, high sensitivity, and advantages for visualizing molecular events in living human tissue. In this review, PET-based radiopharmaceuticals including 18F-FMISO, 18F-FETNIM, 18F-FAZA, and radioactive Cu- ATSM were summarized from published studies about radiosyntheses, pre-clinical data, and clinical data, which are the lead contenders for human application.

The skeleton is one of the most common organs affected by metastatic cancer, and bone metastases often cause severe pain, which significantly affects quality of life. Internal radiotherapy using specifically localized bone-seeking radiopharmaceuticals has proven to be an effective alternative and shows fewer side effects than those associated with other forms of treatment. In this review article, we highlight not only radiopharmaceuticals, which have been approved for the palliation of bone metastases but also boneseeking radiolabeled compounds under investigation in basic research. Specifically, we review the efficacy and prospects of phosphorus- 32, strontium-89 chloride, samarium-153-EDTMP, rhenium-186/188-HEDP, rhenium-186/188-complex conjugated bisphosphonate compounds, yttrium-90-DOTA conjugated bisphosphonate, rhenium-186/188-DMSA, radium-223 chloride, thorium-227-EDTMP, thorium-227-DOTMP, and lead/bismuth-212-DOTMP.

Imaging techniques targeting tumor angiogenesis have been investigated for past decade. Of these, the radiolabeled Arg-Gly- Asp (RGD) peptide has been focused because it has high affinity and selectivity for integrin alpha(v)beta3. Integrin alpha(v)beta3 is expressed on the plasma membrane in an active status in which it binds its ligands and transduce signals when exposed activating external stimuli of tumor angiogenesis such as vascular endothelial growth factor (VEGF). Many linear or cyclic RGD peptides were developed for positron emission tomography (PET). In this review, we focused on currently developed RGD peptides as PET probes for non-invasive detection of integrin alpha(v)beta3 expression.

Noninvasive imaging assessment of tumor cell proliferation could be helpful in the evaluation of tumor growth potential, the degree of malignancy, and could provide an early assessment of treatment response prior to changes in tumor size determined by computed tomography (CT), magnetic resonance imaging (MRI), Positron emission tomography (PET), Single-Photon emission computed tomography (SPECT) or ultrasonography, respectfully. Understanding of tumor proliferative activity, in turn, could aid in the selection of optimal therapy by estimating patient prognosis and selecting the proper management. PET/CT imaging of 18F-fluoro-2- deoxy-glucose (FDG) is recognized as a technology for diagnosing the presence and extent of several cancer types. Recently, radiolabeled glucosamine analogues were introduced as a promising SPECT agent to complement FDG imaging to increase specificity and improve the accuracy of lesion size in oncology applications. Radiolabeled glucosamine analogues were developed to localize in the nuclear components of cells primarily via the hexosamine biosynthetic pathway whereas glucose localizes in the cytoplasm of cells through the glycolytic/TCA pathway. This paper reviews novel kit-based radiolabeled glucosamine analogues for metabolic imaging of tumor lesions. The novel radiolabeled glucosamine analogues may increase the specificity in oncology applications and can influence patient diagnosis, planning and monitoring of cancer treatment.

Uncontrolled cell proliferation is an important hallmark of cancer. Cancer treatment with cytostatic chemodrugs usually results in insignificant changes in tumor size, and thus limits the applications of anatomical imaging modalities for determining the therapeutic efficacy. Positron emission tomography (PET) imaging with cell proliferation probes to assess the clinical outcome during or soon after treatment is becoming acceptable. At present, monitoring DNA synthetic pathways with radiolabeled nucleoside probes that are essential for cell proliferation has been considered a more specific approach to predict tumor response. Among the four nucleosides, thymidine analogues, such as 18F-FLT, have undergone years of development for clinical practice, while cytidine, adenosine and guanosine analogues receive less attention. Recently, several literatures have demonstrated that PET imaging with radiolabeled cytidine and adenosine analogues may have potential to evaluate immune response after chemotherapy, and may enable the prognosis forecast. In this review, we summarize the results of recent preclinical and clinical studies regarding using radiolabeled nucleoside analogues for predicting and monitoring tumor response in cancer treatment. The preparation protocols of these nucleoside scintigraphic probes are also described.

Hydrogen sulphide (H2S) is now viewed as an important endogenous gasotransmitter, which exhibits many beneficial effects on the cardiovascular system. H2S is biosynthesized in mammalian tissues by both non-enzymatic processes and several enzymatic pathways ensured by cystathionine-β-synthase and cystathionine-γ-lyase. H2S is endowed with the antioxidant properties of inorganic and organic sulphites, being a scavenger of reactive oxygen species. Furthermore, H2S triggers other important effects and the activation of ATP-sensitive potassium channels (KATP) accounts for its vasorelaxing and cardioprotective effects. H2S also inhibits smooth muscle proliferation and platelet aggregation. Conversely, the impairment of H2S contributes to the pathogenesis of hypertension and is involved in cardiovascular complications associated with diabetes mellitus. There is also evidence of a link between H2S and endothelial nitric oxide (NO). Recent observations indicate a possible pathogenic link between deficiencies of H2S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H2S led to consider this mediator as “the new NO” and to evaluate new attractive opportunities to develop innovative classes of drugs. In this review, the main roles played by H2S in the cardiovascular system and the first examples of H2S-donor drugs are discussed. Some hybrid drugs are also addressed in this review. In such compounds opportune H2S-releasing moieties are conjugated to well-known drugs to improve their pharmacodynamic profile or to reduce the potential for adverse effects.

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

The clinical treatment of multifactorial pathologies (e.g. cancer, Alzheimer’s disease, psychiatric disorders), is still a major challenge. Many researches have been published dealing with the design of multiple ligands, able to act at the same time towards several targets relevant for a given pathology. In the present review, the clinical results about these compounds have been reported, together with the design strategy adopted, in order to allow a critical evaluation of the outcomes of these efforts. What is emerging is that several effective design strategies of multitarget compounds are available, and the choice among these appears to be dependent on the therapeutic area considered. However, at present, besides multitarget drugs discovered during optimization efforts by means of phenotypic assays, drug coadministrations or fixed dose formulations appear to be more useful therapeutic options than designed multiple ligands; this scenario will change when systems biology will be able to select critical targets, i.e. nodal proteins that should be inhibited in order to obtain a therapeutic action; at this point, the design of multiple ligands will allow a renaissance of medicinal chemistry.

Emerging Anticoagulants by B. Kennedy (3388-3416).
Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.

Naturally occurring nonanolides (synonym decanolides) are a large family of secondary metabolites with an interesting 10- membered macrolide subunit. Metabolites of the nonanolide family have been found to have various biological activities, including cytotoxic, phytotoxic, antimalarial, antifungal, antibacterial, and antimicrofilament activities. An early review of the chemistry and bioactivity of nonanolides was presented in 1996, covering the literature published between 1975 and 1995. During the past decades, the broad spectrum of bioactivity and the intriguing structure of the medium-sized ring in nonanolide analogues have continuously drawn the attention of biologists and natural product and synthetic chemists, resulting in a great number of publications. This review summarizes in whole the recent progress in the field of the nonanolides of natural origin, aiming to give the readers a brief view of the compounds, concerning their natural occurrence, structural elucidation, biological activities, total synthesis, and structure-activity relationships. The article covers the literature published in the period from the beginning of 1996 to July 2011.