The natural phenomenon of drug resistance is a widespread issue that hampers the performance of drugs in many major clinical indications. Antibacterial and antifungal drugs are affected, as well as ...compounds for the treatment of cancer, viral infections, or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, the underlying molecular mechanisms have been identified to understand the emergence of resistance and to overcome this detrimental process. Detailed structural information on the root causes for drug resistance is nowadays frequently available, so next‐generation drugs can be designed that are anticipated to suffer less from resistance. This knowledge‐based approach is essential for fighting the inevitable occurrence of drug resistance.
Resistance is futile: The emergence of drug resistance has far‐reaching consequences for clinical efficacy. This Review presents an analysis of the underlying structural mechanisms of drug resistance across different therapeutic indications and highlights rational approaches to overcome this threat to public health.
Cell-penetrating peptides (CPPs) have emerged as powerful tools in terms of drug delivery. Those short, often cationic peptides are characterized by their usually low toxicity and their ability to ...transport diverse cargos inside almost any kinds of cells. Still, one major drawback is their nonselective uptake making their application in targeted cancer therapies questionable. In this work, we aimed to combine the power of a CPP (sC18) with an integrin-targeting unit (cDKP-f3-RGD). The latter is composed of the Arg-Gly-Asp peptide sequence cyclized via a diketopiperazine scaffold and is characterized by its high selectivity toward integrin αvβ3. The two parts were linked via copper-catalyzed alkyne–azide click reaction (CuAAC), while the CPP was additionally functionalized with either a fluorescent dye or the anticancer drug daunorubicin. Both functionalities allowed a careful biological evaluation of these novel peptide-conjugates regarding their cellular uptake mechanism, as well as cytotoxicity in αvβ3 integrin receptor expressing cells versus cells that do not express αvβ3. Our results show that the uptake follows a “kiss-and-run”-like model, in which the conjugates first target and recognize the receptor, but translocate mainly by CPP mediation. Thereby, we observed significantly more pronounced toxic effects in αvβ3 expressing U87 cells compared to HT-29 and MCF-7 cells, when the cells were exposed to the substances with only very short contact times (15 min). All in all, we present new concepts for the design of cancer selective peptide–drug conjugates.
The double functionalization of carbon-carbon multiple bonds in one-pot processes has emerged in recent years as a fruitful tool for the rapid synthesis of complex molecular scaffolds. This review ...covers the advances in domino reactions promoted by the couple palladium(
ii
)/copper(
ii
), which was proven to be an excellent catalytic system for the functionalization of substrates.
The Pd(
ii
)/Cu(
ii
)-catalysed double functionalization of carbon-carbon multiple bonds in domino processes has emerged in recent years as a fruitful tool for the rapid synthesis of complex molecular scaffolds.
When projection methods are employed to regularize linear discrete ill-posed problems, one implicitly assumes that the discrete Picard condition (DPC) is somehow inherited by the projected problems. ...In this paper we show that, under some assumptions, the DPC holds for the projected uncorrupted systems computed by various Krylov subspace methods. By exploiting the inheritance of the DPC, some estimates on the behavior of the projected problems are also derived. Numerical examples are provided in order to illustrate the accuracy of the derived estimates.
Many successful variational regularization methods employed to solve linear inverse problems in imaging applications (such as image deblurring, image inpainting, and computed tomography) aim at ...enhancing edges in the solution, and often involve non-smooth regularization terms (e.g., total variation). Such regularization methods can be treated as iteratively reweighted least squares problems (IRLS), which are usually solved by the repeated application of a Krylov projection method. This approach gives rise to an inner–outer iterative scheme where the outer iterations update the weights and the inner iterations solve a least squares problem with fixed weights. Recently, flexible or generalized Krylov solvers, which avoid inner–outer iterations by incorporating iteration-dependent weights within a single approximation subspace for the solution, have been devised to efficiently handle IRLS problems. Indeed, substantial computational savings are generally possible by avoiding the repeated application of a traditional Krylov solver. This paper aims to extend the available flexible Krylov algorithms in order to handle a variety of edge-enhancing regularization terms, with computationally convenient adaptive regularization parameter choice. In order to tackle both square and rectangular linear systems, flexible Krylov methods based on the so-called flexible Golub–Kahan decomposition are considered. Some theoretical results are presented (including a convergence proof) and numerical comparisons with other edge-enhancing solvers show that the new methods compute solutions of similar or better quality, with increased speedup.
This review highlights the development of palladium-catalyzed C-H and N-H functionalization reactions involving indole derivatives. These procedures require unactivated starting materials and are ...respectful of the basic principle of sustainable chemistry tied to atom economy.
Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in ...tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified αvβ3 and α5β1 receptors using biotinylated vitronectin (αvβ3) and fibronectin (α5β1) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for αvβ3 over α5β1. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin αvβ3). The two RGD ligands showed IC50 values in the same micromolar range as the reference compound (cycloRGDfV), while for the isoDGR derivative an IC50 value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the αVβ3 integrin active site, provided a rationale for the behavior of these ligands toward the receptor.
A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a ...catalytic amount of CuCl2 and a stoichiometric amount of N-halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reactions can be performed working solely with stoichiometric CuCl2 and CuBr2, respectively.
Antibody-Drug Conjugates (ADCs) and Small Molecule-Drug Conjugates (SMDCs) represent successful examples of targeted drug-delivery technologies for overcoming unwanted side effects of conventional ...chemotherapy in cancer treatment. In both strategies, a cytotoxic payload is connected to the tumor homing moiety through a linker that releases the drug inside or in proximity of the tumor cell, and that represents a key component for the final therapeutic effect of the conjugate. Here, we show that the replacement of the Val-Ala-
p
-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-
p
-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the
cyclo
DKP
-iso
DGR α
V
β
3
integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the “kiss-and-run” protocol, and the relative potency were clearly consistent with the expression of the α
V
β
3
integrin receptor in the considered cancer cell lines.
In vitro
enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems.
Alkenylureas arising from glycine allylamides were proven to be suitable substrates for the synthesis of bicyclic five‐membered ring‐fused piperazinones. The reported intramolecular domino processes, ...performed under oxidative conditions with bis(acetonitrile)palladium dichloride as catalyst and copper(II) chloride in a stoichiometric amount by microwave activation, were completely selective, involving either diamination or aminooxygenation. While the latter process is determined by the direct intervention of the urea oxygen on the σ‐alkylpalladium intermediate, the diamination reaction can in principle derive from a direct attack of the second nitrogen atom on the palladium complex or on the first formed chloromethylpiperazinone. Indeed, this latter species was isolated and proved to be capable of conversion solely into the imidazopiperazinone.
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