Cellular communication among smooth muscle cells: The role of membrane potential via connexins.

Communication via action potentials among neurons has been extensively studied. However, effective communication without action potentials is ubiquitous in biological systems, yet it has received much less attention in comparison. Multi-cellular communication among smooth muscles is crucial for regulating blood flow, for example. Understanding the mechanism of this non-action potential communication is critical in many cases, like synchronization of cellular activity, under normal and pathological conditions. In this paper, we employ a multi-scale asymptotic method to derive a macroscopic homogenized bidomain model from the microscopic electro-neutral (EN) model. This is achieved by considering different diffusion coefficients and incorporating nonlinear interface conditions. Subsequently, the homogenized macroscopic model is used to investigate communication in multi-cellular tissues. Our computational simulations reveal that the membrane potential of syncytia, formed by interconnected cells via connexins, plays a crucial role in propagating oscillations from one region to another, providing an effective means for fast cellular communication. Statement of Significance: In this study, we investigated cellular communication and ion transport in vascular smooth muscle cells, shedding light on their mechanisms under normal and abnormal conditions. Our research highlights the potential of mathematical models in understanding complex biological systems. We developed effective macroscale electro-neutral bi-domain ion transport models and examined their behavior in response to different stimuli. Our findings revealed the crucial role of connexinmediated membrane potential changes and demonstrated the effectiveness of cellular communication through syncytium membranes. Despite some limitations, our study provides valuable insights into these processes and emphasizes the importance of mathematical modeling in unraveling the complexities of cellular communication and ion transport.

Nanoscale Sequential Reactor Design Achieves Effective Removal of Disinfection Byproduct Precursors in Catalytic Ozonation.

Transforming dissolved organic matter (DOM) is a crucial approach to alleviating the formation of disinfection byproducts (DBPs) in water treatment. Although catalytic ozonation effectively transforms DOM, increases in DBP formation potential are often observed due to the accumulation of aldehydes, ketones, and nitro compound intermediates during DOM transformation. In this study, we propose a novel strategy for the sequential oxidation of DOM, effectively reducing the levels of accumulation of these intermediates. This is achieved through the development of a catalyst with a tailored surface and nanoconfined active sites for catalytic ozonation. The catalyst features a unique confinement structure, wherein Mn-N4 moieties are uniformly anchored on the catalyst surface and within nanopores (5-20 Å). This design enables the degradation of the large molecular weight fraction of DOM on the catalyst surface, while the transformed smaller molecular weight fraction enters the nanopores and undergoes rapid degradation due to the confinement effect. The generation of *Oad as the dominant reactive species is essential for effectively reducing these ozone refractory intermediates. This resulted in over 70% removal of carbonaceous and nitrogenous DBP precursors as well as brominated DBP precursors. This study highlights the importance of the nanoscale sequential reactor design and provides new insights into eliminating DBP precursors by the catalytic ozonation process.

A Model of Multi-Finger Coordination in Keystroke Movement.

In multi-finger coordinated keystroke actions by professional pianists, movements are precisely regulated by multiple motor neural centers, exhibiting a certain degree of coordination in finger motions. This coordination enhances the flexibility and efficiency of professional pianists' keystrokes. Research on the coordination of keystrokes in professional pianists is of great significance for guiding the movements of piano beginners and the motion planning of exoskeleton robots, among other fields. Currently, research on the coordination of multi-finger piano keystroke actions is still in its infancy. Scholars primarily focus on phenomenological analysis and theoretical description, which lack accurate and practical modeling methods. Considering that the tendon of the ring finger is closely connected to adjacent fingers, resulting in limited flexibility in its movement, this study concentrates on coordinated keystrokes involving the middle and ring fingers. A motion measurement platform is constructed, and Leap Motion is used to collect data from 12 professional pianists. A universal model applicable to multiple individuals for multi-finger coordination in keystroke actions based on the backpropagation (BP) neural network is proposed, which is optimized using a genetic algorithm (GA) and a sparrow search algorithm (SSA). The angular rotation of the ring finger's MCP joint is selected as the model output, while the individual difference information and the angular data of the middle finger's MCP joint serve as inputs. The individual difference information used in this study includes ring finger length, middle finger length, and years of piano training. The results indicate that the proposed SSA-BP neural network-based model demonstrates superior predictive accuracy, with a root mean square error of 4.8328°. Based on this model, the keystroke motion of the ring finger's MCP joint can be accurately predicted from the middle finger's keystroke motion information, offering an evaluative method and scientific guidance for the training of multi-finger coordinated keystrokes in piano learners.

Identification of Critical Links Based on Electrical Betweenness and Neighborhood Similarity in Cyber-Physical Power Systems.

Identifying critical links is of great importance for ensuring the safety of the cyber-physical power system. Traditional electrical betweenness only considers power flow distribution on the link itself, while ignoring the local influence of neighborhood links and the coupled reaction of information flow on energy flow. An identification method based on electrical betweenness centrality and neighborhood similarity is proposed to consider the internal power flow dynamic influence existing in multi-neighborhood nodes and the topological structure interdependence between power nodes and communication nodes. Firstly, for the power network, the electrical topological overlap is proposed to quantify the vulnerability of the links. This approach comprehensively considers the local contribution of neighborhood nodes, power transmission characteristics, generator capacity, and load. Secondly, in communication networks, effective distance closeness centrality is defined to evaluate the importance of communication links, simultaneously taking into account factors such as the information equipment function and spatial relationships. Next, under the influence of coupled factors, a comprehensive model is constructed based on the dependency relationships between information flow and energy flow to more accurately assess the critical links in the power network. Finally, the simulation results show the effectiveness of the proposed method under dynamic and static attacks.

Synthesis and discovery of Baylis-Hillman adducts as potent and selective thioredoxin reductase inhibitors for cancer treatment.

The selenoprotein thioredoxin reductase (TrxR) is of paramount importance in maintaining cellular redox homeostasis, and aberrant upregulation of TrxR is frequently observed in various cancers due to their elevated oxidative stress in cells. Thus, it seems promising and feasible to target the ablation of intracellular TrxR for the treatment of cancers. We report herein the design and synthesis of a series of Baylis-Hillman adducts, and identified a typical adduct that possesses the superior cytotoxicity against HepG2 cells over other types of cancer cells. The biological investigation shows the selected typical adduct selectively targets TrxR in HepG2 cells, which thereafter results in the collapse of intracellular redox homeostasis. Further mechanistic studies reveal that the selected typical adduct arrests the cell cycle in G1/G0 phase. Importantly, the malignant metastasis of HepG2 cells is significantly restrained by the selected typical adduct. With well-defined molecular target and mechanism of action, the selected typical adduct, even other Baylis-Hillman skeleton-bearing compounds, merits further development as candidate or ancillary agent for the treatment of various cancers.

Progress and perspective on hydrogen sulfide donors and their biomedical applications.

Following the discovery of nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2 S) has been identified as the third gasotransmitter in humans. Increasing evidence have shown that H2 S is of preventive or therapeutic effects on diverse pathological complications. As a consequence, it is of great significance to develop suitable approaches of H2 S-based therapeutics for biomedical applications. H2 S-releasing agents (H2 S donors) play important roles in exploring and understanding the physiological functions of H2 S. More importantly, accumulating studies have validated the theranostic potential of H2 S donors in extensive repertoires of in vitro and in vivo disease models. Thus, it is imperative to summarize and update the literatures in this field. In this review, first, the background of H2 S on its chemical and biological aspects is concisely introduced. Second, the studies regarding the H2 S-releasing compounds are categorized and described, and accordingly, their H2 S-donating mechanisms, biological applications, and therapeutic values are also comprehensively delineated and discussed. Necessary comparisons between related H2 S donors are presented, and the drawbacks of many typical H2 S donors are analyzed and revealed. Finally, several critical challenges encountered in the development of multifunctional H2 S donors are discussed, and the direction of their future development as well as their biomedical applications is proposed. We expect that this review will reach extensive audiences across multiple disciplines and promote the innovation of H2 S biomedicine.

Novel insights into the interaction reactive components and synergistic fouling mechanisms of ultrafiltration by natural organic matter fractions and kaolin.

The mechanisms governing interactions among various natural organic matter (NOM) fractions and the subsequently impact on ultrafiltration process have not been systematically studied. In this work, bovine serum albumin (BSA), humic acid (HA), sodium alginate (SA) were applied as model NOM to explore the influence of the interactions among NOM on ultrafiltration process. Results indicated that tryptophan-like fluorescence fraction was the dominant reaction fraction of HA to react with SA and BSA. Different interactions among model NOM not only changed the interception order of fluorescence fractions by ultrafiltration from fulvic acid-like, humic-like and tryptophan-like in BSA/HA mixture to tryptophan-like, humic-like and fulvic acid-like in BSA/HA/SA/kaolin mixture, but also remarkably influence the membrane fouling behavior. In BSA/HA mixture, new-generated aggregates with molecular weight (MW) of 10 kDa could not pass though ultrafiltration membrane and mainly contributed to chemical reversible fouling. In BSA/HA/SA mixture, SA simultaneously reacted with BSA and HA to generate aggregates with larger MW which could be washed down by physical cleaning. In BSA/HA/SA/kaolin mixture, the aggregates with MW of 10 kDa and chemical reversible fouling were disappeared due to the adsorption role of kaolin. These findings could further improve our understanding regarding membrane fouling mechanisms of raw water with different components.

Energy-efficient removal of carbamazepine in solution by electrocoagulation-electrofenton using a novel P-rGO cathode.

In this study, carbamazepine (CBZ) decay in solution has been studied by coupling electrocoagulation with electro-Fenton (EC-EF) with a novel P-rGO/carbon felt (CF) cathode, aiming to accelerate the in-situ generation of •OH, instead of adding Fe2+ and H2O2. Firstly, the fabricated P-rGO and its derived cathode were characterized by XRD, SEM, AFM, XPS and electrochemical test (EIS, CV and LSV). Secondly, it was confirmed that the performance in removal efficiency and electric energy consumption (EEC) by EC-EF (kobs=0.124 min-1, EEC=43.98 kWh/kg CBZ) was better than EF (kobs=0.069 min-1, EEC=61.04 kWh/kg CBZ). Then, P-rGO/CF (kobs=0.248 min-1, EEC=29.47 kWh/kg CBZ, CE=61.04%) showed the best performance in EC-EF, among all studied heteroatom-doped graphene/CF. This superior performance may be associated with its largest layer spacing and richest C=C, which can promote the electron transfer rate and conductivity of the cathode. Thus, more H2O2 and •OH could be produced to degrade CBZ, and almost 100% CBZ was removed with kobs being 0.337 min-1 and the EEC was only 24.18 kWh/kg CBZ, under the optimal conditions (P-rGO loading was 6.0 mg/cm2, the current density was 10.0 mA/cm2, the gap between electrode was 2.0 cm). Additionally, no matter the influent is acidic, neutral or alkaline, no additional pH adjustment is required for the effluent of EC-EF. At last, an inconsecutive empirical kinetic model was firstly established to predict the effect of operating parameters on CBZ removal.

Small molecules regulating reactive oxygen species homeostasis for cancer therapy.

Elevated intracellular reactive oxygen species (ROS) and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. Compared with normal cells, cancer cells exhibit increased ROS to maintain their malignant phenotypes and are more dependent on the "redox adaptation" mechanism. Thus, there are two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to prevent or treat cancer. The first strategy, that is, chemoprevention, is to prevent or reduce intracellular ROS either by suppressing ROS production pathways or by employing antioxidants to enhance ROS clearance, which protects normal cells from malignant transformation and inhibits the early stage of tumorigenesis. The second strategy is the ROS-mediated anticancer therapy, which stimulates intracellular ROS to a toxicity threshold to activate ROS-induced cell death pathways. Therefore, targeting the regulation of intracellular ROS-related pathways by small-molecule candidates is considered to be a promising treatment for tumors. We herein first briefly introduce the source and regulation of ROS, and then focus on small molecules that regulate ROS-related pathways and show efficacy in cancer therapy from the perspective of pharmacophores. Finally, we discuss several challenges in developing cancer therapeutic agents based on ROS regulation and propose the direction of future development.

Oat polyphenol avenanthramide-2c confers protection from oxidative stress by regulating the Nrf2-ARE signaling pathway in PC12 cells.

Accumulating evidence has demonstrated that cellular antioxidant systems play essential roles in retarding oxidative stress-related diseases, such as Parkinson's disease. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is a chief regulator of cellular antioxidant systems, small molecules with Nrf2-activating ability may be promising neuroprotective agents. Avenanthramide-2c (Aven-2c), avenanthramide-2f (Aven-2f) and avenanthramide-2p (Aven-2p) are the most abundant avenanthramides in oats, and they have been documented to possess multiple pharmacological benefits. In this work, we synthesized these three compounds and evaluated their cytoprotective effect against oxidative stress-induced PC12 cell injuries. Aven-2c displayed the best protective potency among them. Aven-2c conferred protection on PC12 cells by scavenging free radicals and activating the Nrf2-ARE signaling pathway. Pretreatment of PC12 cells with Aven-2c efficiently enhanced Nrf2 nuclear accumulation and evoked the expression of a set of cytoprotective molecules. The mechanistic study also supports that Nrf2 activation is the molecular basis for the cellular action of Aven-2c. Collectively, this study demonstrates that Aven-2c is a potent Nrf2 agonist, shedding light on the potential usage of Aven-2c in the treatment of neuroprotective diseases.

Streptochlorin analogues as potential antifungal agents: Design, synthesis, antifungal activity and molecular docking study.

Streptochlorin is a small molecule of indole alkaloid isolated from marine Streptomyces sp., it is a promising lead compound due to its potent bioactivity in preventing many phytopathogens in our previous study, but further structural modifications are required to improve its antifungal activity. Our work in this paper focused on the replacement of oxazole ring in streptochlorin with the imidazole ring, to discover novel analogues. Based on this design strategy, three series of streptochlorin analogues were efficiently synthesized through sequential Vilsmeier-Haack reaction, Van Leusen imidazole synthesis and halogenation reaction. Some of the analogues displayed excellent activity in the primary assays, and this is highlighted by compounds 4g and 4i, the growth inhibition against Alternaria Leaf Spot and Rhizoctorzia solani under 50 µg/mL are 97.5% and 90.3%, respectively, even more active than those of streptochlorin, pimprinine and Osthole. Molecular docking models indicated that streptochlorin binds with Thermus thermophiles Leucyl-tRNA Synthetase in a similar mode to AN2690, offering a perspective on the mode of action study for antifungal activities of streptochlorin derivatives. Further study is still ongoing with the aim of discovering synthetic analogues, with improved antifungal activity and clear mode of action.

Generation of potent Nrf2 activators via tuning the electrophilicity and steric hindrance of vinyl sulfones for neuroprotection.

Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stress via transcriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H2O2-mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds 9b and 9c with marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of 9b and 9c, arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together, 9b and 9c discovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.

Synthesis and biological evaluation of disulfides as anticancer agents with thioredoxin inhibition.

Altered redox homeostasis as a hallmark of cancer cells is exploited by cancer cells for growth and survival. The thioredoxin (Trx), an important regulator in maintaining the intracellular redox homeostasis, is cumulatively recognized as a promising target for the development of anticancer drugs. Herein, we synthesized 72 disulfides and evaluated theirinhibition for Trx and antitumor activity. First, we established an efficient and fast method to screen Trx inhibitors by using the probe NBL-SS that was developed by our group to detect Trx function in living cells. After an initial screening of the Trx inhibitory activity of these compounds, 8 compounds showed significant inhibition activity against Trx. We then evaluated the cytotoxicity of these 8 disulfides, compounds 68 and 69 displayed high cytotoxicity to HeLa cells, but less sensitive to normal cell lines. Next, we performed kinetic studies of both two disulfides, 68 had faster inhibition of Trx than 69. Further studies revealed that 68 led to the accumulation of reactive oxygen species and eventually induced apoptosis of Hela cells via inhibiting Trx. The establishment of a method for screening Trx inhibitors and the discovery of 68 with remarkable Trx inhibition provide support for the development of anticancer candidates with Trx inhibition.

Diversity-oriented synthesis and antifungal activities of novel pimprinine derivative bearing a 1,3,4-oxadiazole-5-thioether moiety.

Based on the strategy of diversity-oriented synthesis and the structures of natural product pimprinine and streptochlorin, two series of novel pimprinine derivatives containing 1,3,4-oxadiazole-5-thioether moieties were efficiently synthesized under the optimized reaction conditions. Biological assays conducted at Syngenta showed the designed derivatives displayed an altered pattern of biological activity, of which 5h was identified as the most promising compound with strong activity against Pythium dissimile and also a broad antifungal spectrum in primary screening. Further structural optimization of pimprinine and streptochlorin derivatives is well under way, aiming to discover synthetic analogues with improved antifungal activity. Two series of novel pimprinine derivatives containing 1,3,4-oxadiazole-5-thioether moieties were efficiently synthesized through diversity-oriented synthesis strategy under the optimized conditions. Biological assays showed the designed derivatives exhibited potential activity.

Occurrence and risk assessment of volatile halogenated disinfection by-products in an urban river supplied by reclaimed wastewater.

The reuse of the sewage is an effective way to solve the shortage of water resources, but disinfection by-products (DBPs) caused by chlorination may bring potential ecological and health risks to the supplied water. In this study, the occurrence and potential ecological risk of DBPs in SH River in Beijing were evaluated. Four kinds of DBPs were detected in 84 samples by GC-MS, including THM, CH, CTC and TCAN, whose detection rates were 100%, 100%, 100% and 2.38%, respectively. Combining with the relevant standard limitation and corresponding threshold values in China, and the reported concentration in domestic and foreign literatures, the results showed that the number of samples which [THM], [CTC] and [CH] exceeded the threshold values in relevant standard for 23.81%, 100.00% and 89.29%, respectively. CTC showed the highest excess times than the threshold value with [CTC]max was 356.46 µg/L. In addition, the temporal and spatial characteristics of identified DBPs were studied. [THM], [CTC] and [CH] all exhibited the highest concentration in Aug., which was as the same as the variation trend of air and water temperature. With the increase of sampling distance, [THM] and [CTC] fluctuated greatly, and the background values in SH River were higher due to the supplement of the reclaimed water. [CH] and [TCAN] gradually decreased, which may be due to that they were more prone to volatilize in the channel and be degraded by aquatic microorganisms. In addition, the occurrence situation in S2 and S7, were in the order of CTC > CH > THM. Hence, the rank of the occurrence situation of identified DBPs was CTC > CH > THM > TCAN. Multivariate analysis showed that THM was significantly positively correlated with CTC and their sources were similar. Moreover, they were all affected by solution pH and DO. Potential ecological risk assessment indicated that the rank of identified DBPs ecological risk was CTC > THM > CH > TCAN. Among them, the risk level of CTC and THM were high in both daily and extreme situations. Therefore, the potential ecological risk caused by DBPs should be fully considered in the process of reclaimed water supplying landscape water, such as urban river. If a higher level of the ecological risk management is needed, THM, CTC and CH, especially CTC, should be considered firstly.

Electric discharge of electrocytes: Modelling, analysis and simulation.

In this paper, we investigate the electric discharge of electrocytes by extending our previous work on the generation of electric potential. We first give a complete formulation of a single cell unit consisting of an electrocyte and a resistor, based on a Poisson-Nernst-Planck (PNP) system with various membrane currents as interfacial conditions for the electrocyte and a Maxwell's model for the resistor. Our previous work can be treated as a special case with an infinite resistor (or open circuit). Using asymptotic analysis, we simplify our PNP system and reduce it to an ordinary differential equation (ODE) based model. Unlike the case of an infinite resistor, our numerical simulations of the new model reveal several distinct features. A finite current is generated, which leads to non-constant electric potentials in the bulk of intracellular and extracellular regions. Furthermore, the current induces an additional action potential (AP) at the non-innervated membrane, contrary to the case of an open circuit where an AP is generated only at the innervated membrane. The voltage drop inside the electrocyte is caused by an internal resistance due to mobile ions. We show that our single cell model can be used as the basis for a system with stacked electrocytes and the total current during the discharge of an electric eel can be estimated by using our model.

Electric potential generation of electrocytes: Modelling, analysis, and computation.

In this paper, we developed a one-dimensional model for electric potential generation of electrocytes in electric eels. The model is based on the Poisson-Nernst-Planck system for ion transport coupled with membrane fluxes including the Hodgkin-Huxley type. Using asymptotic analysis, we derived a simplified zero-dimensional model, which we denote as the membrane model in this paper, as a leading order approximation. Our analysis provides justification for the assumption in membrane models that electric potential is constant in the intracellular space. This is essential to explain the superposition of two membrane potentials that leads to a significant transcellular potential. Numerical simulations are also carried out to support our analytical findings.

Insights into Heteroatom-Doped Graphene for Catalytic Ozonation: Active Centers, Reactive Oxygen Species Evolution, and Catalytic Mechanism.

To guide the design of novel graphene-based catalysts in catalytic ozonation for micropollutant degradation, the mechanism of catalytic ozonation with heteroatom-doped graphene was clarified. Reduced graphene oxide doped with nitrogen, phosphorus, boron, and sulfur atoms (N-, P-, B-, and S-rGO) were synthesized, and their catalytic ozonation performances were evaluated in the degradation of refractory organics and bromate elimination simultaneously. Doping with heteroatoms, except sulfur, significantly improved the catalytic ozonation activity of graphene. Introducing sulfur atoms destroyed the stability of graphene during ozonation, with the observed partial performance improvement caused by surface adsorption. Degradation pathways for selected refractory organics were proposed based on the intermediates identified using high-resolution Orbitrap mass spectroscopy and gas chromatographic-mass spectroscopy. Three and six new unopened intermediates were identified in benzotriazole and p-chlorobenzoic acid degradation, respectively. Roles of chemical functional groups, doped atoms, free electron, and delocalized π electron of heteroatom-doped graphene in catalytic ozonation were identified, and contributions of these active centers to the formation of reactive oxygen species (ROS), including hydroxyl radicals, superoxide radicals, singlet oxygen, and H2O2, were evaluated. A mechanism for catalytic ozonation by heteroatom-doped graphene was proposed for the first time.

Cyanobacteria derived taste and odor characteristics in various lakes in China: Songhua Lake, Chaohu Lake and Taihu Lake.

In recent years, increasing eutrophication in large freshwater lakes, which are an important drinking water source for cities in China, have been resulted in substantial cyanobacteria blooms that could cause serious taste and odor (T&O) problems. In this investigation, three typical lakes (Songhua Lake, Chaohu Lake and Taihu Lake) as drinking water sources located in different geographical areas in China, were selected to study the problems of cyanobacteria-derived T&O (i.e., 2-methylisobornoel, geosmin, ß-ionone, 2-isopropyl-3-methoxypyrazine, 2-isobutyl-3-methoxypyrazine, and 2-methylbenzofuran). The occurrence of T&O in target lakes was compared across various nutrition states and geographic locations, to get more information for early warning for algal bloom and T&O occurrence, being useful lake water management and purification. Results show that the occurrence of T&O in Songhua Lake was the poorest for the lowest nutrient state, as a first report in T&O research field in China. This is a lake located in Northeast China at high latitude, with lower water temperatures. The occurrence of T&O in Chaohu Lake was ranked in the middle. That in Taihu Lake was the most intensive. Finally, the relationship between water quality, T&O and its origin was analyzed by multivariate statistical methods (correlation analysis, principal component, and cluster analyses).

Design, synthesis, and cytotoxic activity of novel 7-substituted camptothecin derivatives incorporating piperazinyl-sulfonylamidine moieties.

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN. Especially, compounds 13r and 13p (IC50 0.38 and 0.85µM, respectively) displayed the greatest cytotoxicity against the MDR KB-VIN cell line and merit further development into preclinical and clinical drug candidates for treating cancer, including MDR phenotype.