Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation

A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The CAPAC platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)-modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels–Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapies. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. In mice, the maximum tolerated dose (MTD) of SQP33 in combination with locally injected tetrazine-modified biopolymer (SQL70) was determined to be 19.1-times the MTD of conventional doxorubicin. Pharmacokinetics studies in rats show that a single injection of SQL70 efficiently captures multiple SQP33 protodrug doses given cumulatively at 10.8-times the MTD of conventional doxorubicin with greatly reduced systemic toxicity. Finally, combined treatment with SQL70 and SQP33 (together called SQ3370) showed antitumor activity in a syngeneic tumor model in mice.

The Click Activated Protodrugs Against Cancer (CAPAC) platform uses click chemistry to activate cytotoxic drugs directly at a target site with minimal toxicity, overcoming limitations of conventional chemotherapy and traditional targeted therapies.     

Improvement of cytotoxic activity of local anesthetics against human breast cancer cell line through the cyclodextrin complexes

Among the potent anticancer agents, Local Anesthetics (LA) have been found to be efficient against many different types of cancer cells. However, the major disadvantage associated with the use of LA its low systemic bioavailability when administered due to its poor aqueous solubility. Our present work concentrates on improving the bio-availability by complexing with cyclodextrin. We synthesized the inclusion complexion by co-precipitation method which is an efficient method among other and characterized the formulation of complex by UV and fluorescence studies. The in-vitro study of cytotoxicity against breast cancer cell line is performed. Our study shows the formation of the complex with 1:1 ratio and the result show both Benzocaine and Tetracaine inclusion complex has higher potential towards breast cancer cell than the free drug.     

Rapid and quantitative method for evaluating the personal therapeutic potential of cancer drugs

An in vitro, rapid, and quantitative cell-based assay is needed to predict the efficacy of cancer drugs in individual patients, because a cancer patient may have unconventional aspects of tumor development. Here we report a rapid and label-free quantitative method for verifying apoptosis in living cancer cells cultured on a sensor chip with a newly developed high-precision surface plasmon resonance (SPR) sensor. The time-course cell reaction was monitored as the SPR angle change rate for 5 min during a 35-min cell culture of pancreatic cancer lines with a drug. The time-course cell reaction was significantly related to cell viability counted after 48 h as assessed by caspase-3 activity assay of apoptosis. Furthermore, the detected SPR signal was derived from the decrease in inner mitochondrial membrane potential. The results obtained are universally valid for various cancer drugs mediating apoptosis through different cell-signaling pathways and even for combined use in various pancreatic cancer cell lines. This system can be applied in a clinical setting to evaluate the personal therapeutic potential of drugs including pharmacodynamic interactions.     

Exploring and exploiting the therapeutic potential of glycoconjugates

Carbohydrates, either bound to proteins or in lipids, play essential roles as communication molecules in many intercellular and intracellular processes. In particular, carbohydrates are important mediators of cell-cell recognition events and have been implicated in related processes such as cell signaling regulation, cellular differentiation and immune response. This diverse utility has long suggested the power of carbohydrates in therapeutic approaches. This Concepts article highlights the recent potential uses of glycoconjugates as therapeutics, with particular reference to glycopeptides, glycoproteins, glycodendrimers, and glycoarrays.     

Synthesis of a porphyrin-labelled carboranyl phosphate diester: a potential new drug for boron neutron capture therapy of cancer

A boron-rich, water-soluble porphyrin conjugate was synthesized by coupling of two carboranyl alcohols with 2-chlorophenoxyphosphorus dichloride, followed by conjugation to an amine-functionalized tetraphenyl-porphyrin via an amide linkage.     

Correction to: Elucidating the therapeutic activity of selective curcumin analogues: DFT-based reactivity analysis

Structural Chemistry - A Correction to this paper has been published: https://doi.org/10.1007/s11224-021-01788-w     

Click Polyester: Synthesis of Polyesters Containing Triazole Units in the Main Chain by Click Chemistry and Improved Thermal Property

A “click” polymerization of dialkynes that contain an ester linkages and diazides to has been performed to synthesize various polyesters, termed “click polyesters” with a high of 1.0 × 10⁴ to 7.0 × 10⁴ in an excellent yield. This polymerization accompanied a formation of 1,4‐disubstituted triazoles in the polyester main chain by a Cu^I catalyst. The triazole ring formation in the polyester main chain leads to improved thermal properties and enhancement of the even–odd effect of methylene chain length of the produced click polyesters. This report is the first report of the application of click chemistry to synthesize a series of polyesters under mild conditions.

     

Drug repurposing approach for the identification and designing of potential E6 inhibitors against cervical cancer: an in silico investigation

Structural Chemistry - Repurposing of ‘old’ drugs to treat both common and rare diseases has garnered huge attention of the researchers because of the high attrition rates and...     

Resonant electron capture negative ion mass spectrometry: the state of the art and the potential for solving analytical problems

Russian Chemical Bulletin - Resonant electron capture negative ion mass spectrometry (REC NI MS) is a highly informative method of investigation of low-energy electron-molecule reactions,...     

Preparation of activated carbon from date pits: Effect of the activation agent and liquid phase oxidation

Two series of activated carbons have been prepared from date pits; series C, using carbon dioxide as activating agent, and series S, prepared by activation with steam under the same experimental conditions. The obtained samples were oxidized with nitric acid in order to introduce more oxygen surface groups. The surface area and porosity of the parent and oxidized activated carbons were studied by N₂ adsorption at 77 K and CO₂ adsorption at 273 K. The oxygen surface complexes were characterized by temperature-programmed decomposition (TPD). The results show that carbon dioxide and steam activations produce microporous carbons with an increasing amount of CO evolving groups when increasing the burn-off. On the other hand, oxidation with nitric acid increases the amount of CO and CO₂ evolved by the decomposition of surface oxygen groups, this increase being related to the development of porosity in the carbon with the degree of activation and to the activating agent used (CO₂ versus steam).     

In situ neutron activation analysis of and the neutron capture cross-section for90Sr+

Neutron activation analysis has been investigated as an in situ method for determination of⁹⁰Sr. The thermal neutron capture cross-section for the⁹⁰Sr(n, γ)⁹¹Sr reaction has been measured to be 14.0±2.4 mb which is in disagreement with the currently accepted literature value. The suitability of this reaction and the fast neutron reactions⁹⁰Sr(n, p)⁹⁰Rb and⁹⁰Sr(n, α)⁸⁷Kr, for the in situ determination of⁹⁰Sr is discussed.     

A passage through systems biology to systems medicine: adoption of middle-out rational approaches towards the understanding of therapeutic outcomes in cancer

During the last few decades, conventional practices in medicine including oncology focus their interests towards the reductionism of molecular detailing and at the analytical level population-based assessment with stochastic principles, technically called 'evidence-based medicine', is generally practiced. Due to fluctuations in physiological parameters, the analysis and prediction of a therapeutic outcome in cancer on an individual level is uncertain. In recent times the well accepted opinion is that cancer should be looked upon as a systems disorder. This makes a paradigm shift - from a fragmented to a systems approach, linear to nonlinear methodology and from genome to physiome based analysis to understand the cancer. In the arena of systems biology, different groups have different views, namely, bottom-up (mechanistic), top-down (operational) and middle-out (rational). With respect to cancer each has a special relevance to serve the specific objectivity. In this article we have reviewed the views of the different schools, recent developments and controversies associated with the uncertainties in prediction of the therapeutic outcome of cancer. Recent advances in dynamical science and control theory may provide suitable analytical tools for capturing the uncertainties associated with cancer therapy through the development of middle-out rationalist (MORA) views.     

The therapeutic potential of metal-based antimalarial agents: implications for the mechanism of action

Despite recent encouraging advances against the disease, malaria remains a major public health problem affecting almost half a billion people and killing almost a million per annum. Due to a short arsenal of efficient antimalarial agents and the frequent appearance of resistance to the drugs in current use, which consequently reduce our means to treat patients, there is a very urgent and continuous need to develop new compounds. This perspective outlines a unique strategy for that purpose through the development of metal-based antimalarial agents. The examples presented here illustrate an attractive alternative to classical drugs.     

Palladium(II) N-heterocyclic carbene complexes: synthesis,structures and cytotoxicity potential studies against breast cancer cell line

Abstract

Mononuclear trans-Pd(II)–NHC complexes (where NHC?=?N-heterocyclic carbene) bearing asymmetrically substituted NHC-ligand have been synthesized via transmetalation reaction between Ag(I)–NHC complexes and [Pd(NCCH₃)₂Cl₂]. The NHC precursors are accessible in two steps by N-n-alkyl reactions of benzimidazole. The resultant benzimidazolium salts were deprotonated with Ag₂O by in situ deprotonation to facilitate the formation of mononuclear Ag(I)–NHC complexes. Single-crystal structural study for Pd(II)–NHC shows that the palladium(II) ion exhibits a square-planar geometry of two NHC ligands and two chloride ions. The cytotoxicity study was investigated against breast cancer cell line (MCF-7). The Ag(I)–NHC complexes exhibit better activities than their corresponding Pd(II)–NHC complexes, whereas all benzimidazolium salts are inactive toward MCF-7 cancer cell line.     

Roles and potential therapeutic targets of the ubiquitin proteasome system in muscle wasting

Muscle wasting, characterized by the loss of protein mass in myofibers, is in most cases largely due to the activation of intracellular protein degradation by the ubiquitin proteasome system (UPS). During the last decade, mechanisms contributing to this activation have been unraveled and key mediators of this process identified. Even though much remains to be understood, the available information already suggests screens for new compounds inhibiting these mechanisms and highlights the potential for pharmaceutical drugs able to treat muscle wasting when it becomes deleterious. This review presents an overview of the main pathways contributing to UPS activation in muscle and describes the present state of efforts made to develop new strategies aimed at blocking or slowing muscle wasting. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).     

Effects of activation conditions on the structural and adsorption characteristics of pinecones derived activated carbons

This study was conducted to understand and optimize the activation process for the production of a low-cost activated carbon (AC) using a renewable and plentiful biomass waste, pinecones. This was achieved by tracking the changes in porous structure, surface chemistry and adsorption properties of the AC produced using different activating agents, activation temperatures, holding times and heating rates. Generally, produced ACs were predominantly microporous with small external surface area and were different in terms of H/C and O/C ratios. Study of Pb²⁺ cations adsorption on these samples proved the high affinity of the pinecones derived ACs to this cation. The best adsorption behaviour was recognized in sample prepared by impregnation with H₃PO₄ at weight ratio of 2, then heating at 400?°C for 2?h at 5?°C/min heating rate. This sample possessed the highest BET surface area (1335 m²/g). The adsorption process obeyed the pseudo-first-order and Freundlich model slightly better than the pseudo-second-order kinetics and Langmuir model. The high Langmuir maximum adsorption capacity of 418?mg/g supports the applicability of the produced AC for the removal of Pb²⁺ cations from wastewater.