Drug Development Research最新文献

{"title":"Unveiling the potential of antisense oligonucleotides: Mechanisms, therapies, and safety insights","authors":"Edanur Ersöz,&nbsp;Devrim Demir-Dora","doi":"10.1002/ddr.22187","DOIUrl":"10.1002/ddr.22187","url":null,"abstract":"<p>Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded deoxynucleotide sequences composed of phosphate backbone-connected sugar rings. Designing of those strands is based on Watson-Crick hydrogen bonding mechanism. Thanks to rapidly advancing medicine and technology, evolving of the gene therapy area and ASO approaches gain attention. Considering the genetic basis of diseases, it is promising that gene therapy approaches offer more specific and effective options compared to conventional treatments. The objective of this review is to explain the mechanism of ASOs and discuss the characteristics and safety profiles of therapeutic agents in this field. Pharmacovigilance for gene therapy products is complex, requiring accurate assessment of benefit-risk balance and evaluation of adverse effects.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of ROS and KEAP1-related genes and verified targets of α-hederin induce cell death for CRC","authors":"Gang Wang,&nbsp;Zhi-Min Zhu,&nbsp;Kun Wang","doi":"10.1002/ddr.22200","DOIUrl":"10.1002/ddr.22200","url":null,"abstract":"<p>In this study, we analyzed and verified differentially expressed genes (DEGs) in ROS and KEAP1 crosstalk in oncogenic signatures using GEO data sets (GSE4107 and GSE41328). Multiple pathway enrichment analyses were finished based on DEGs. The genetic signature for colorectal adenocarcinoma (COAD) was identified by using the Cox regression analysis. Kaplan–Meier survival and receiver operating characteristic curve analysis were used to explore the prognosis value of specific genes in COAD. The potential immune signatures and drug sensitivity prediction were also analyzed. Promising small-molecule agents were identified and predicted targets of α-hederin in SuperPred were validated by molecular docking. Also, expression levels of genes and Western blot analysis were conducted. In total, 48 genes were identified as DEGs, and the hub genes such as COL1A1, CXCL12, COL1A2, FN1, CAV1, TIMP3, and IGFBP7 were identified. The ROS and KEAP1-associated gene signatures comprised of hub key genes were developed for predicting the prognosis and evaluating the immune cell responses and immune infiltration in COAD. α-hederin, a potential anti-colorectal cancer (CRC) agent, was found to enhance the sensitivity of HCT116 cells, regulate CAV1 and COL1A1, and decrease KEAP1, Nrf2, and HO-1 expression significantly. KEAP1-related genes could be an essential mediator of ROS in CRC, and KEAP1-associated genes were effective in predicting prognosis and evaluating individualized CRC treatment. Therefore, α-hederin may be an effective chemosensitizer for CRC treatments in clinical settings.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of novel tetrabromophthalimide derivatives as potential tubulin inhibitors endowed with apoptotic induction for cancer treatment","authors":"Marwa Abdel-Motaal,&nbsp;Dalal A. Aldakhili,&nbsp;Ayman Abo Elmaaty,&nbsp;Marwa Sharaky,&nbsp;Mai A. E. Mourad,&nbsp;Abdullah Y. A. Alzahrani,&nbsp;Nadia A. Mohamed,&nbsp;Ahmed A. Al-Karmalawy","doi":"10.1002/ddr.22197","DOIUrl":"10.1002/ddr.22197","url":null,"abstract":"<p>Although various approaches exist for treating cancer, chemotherapy continues to hold a prominent role in the management of this disease. Besides, microtubules serve as a vital component of the cellular skeleton, playing a pivotal role in the process of cell division making it an attractive target for cancer treatment. Hence, the scope of this work was adapted to design and synthesize new anti-tubulin tetrabromophthalimide hybrids (<b>3</b>-<b>17</b>) with colchicine binding site (CBS) inhibitory potential. The conducted in vitro studies showed that compound <b>16</b> displayed the lowest IC₅₀ values (11.46 µM) at the FaDu cancer cell lines, whereas compound <b>17</b> exhibited the lowest IC₅₀ value (13.62 µM) at the PC3 cancer cell line. However, compound <b>7b</b> exhibited the lowest IC₅₀ value (11.45 µM) at the MDA-MB-468 cancer cell line. Moreover, compound <b>17</b> was observed to be the superior antitumor candidate against all three tested cancer cell lines (MDA-MB-468, PC3, and FaDu) with IC₅₀ values of 17.22, 13.15, and 13.62 µM, respectively. In addition, compound <b>17</b> showed a well-established upregulation of apoptotic markers (Caspases 3, 7, 8, and 9, Bax, and P53). Moreover, compound <b>17</b> induced downregulation of the antiapoptotic markers (MMP2, MMP9, and BCL-2). Furthermore, the colchicine binding site inhibition assay showed that compounds <b>15a</b> and <b>17</b> exhibited particularly significant inhibitory potentials, with IC₅₀ values of 23.07 and 4.25 µM, respectively, compared to colchicine, which had an IC₅₀ value of 3.89 µM. Additionally, cell cycle analysis was conducted, showing that compound <b>17</b> could prompt cell cycle arrest at both the G0-G1 and G2-M phases. On the other hand, a molecular docking approach was applied to investigate the binding interactions of the examined candidates compared to colchicine towards CBS of the β-tubulin subunit. Thus, the synthesized tetrabromophthalimide hybrids can be regarded as outstanding anticancer candidates with significant apoptotic activity.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noscapine modulates hypoxia-induced angiogenesis and hemodynamics: Insights from a zebrafish model investigation","authors":"Jhansi Nathan,&nbsp;Rabiathul Shameera,&nbsp;Kaniha Sivakumar,&nbsp;Soundarya Rajendran,&nbsp;Elumalai Perumal","doi":"10.1002/ddr.22195","DOIUrl":"https://doi.org/10.1002/ddr.22195","url":null,"abstract":"<p>We investigated the angiogenesis-modulating ability of noscapine in vitro using osteosarcoma cell line (MG-63) and in vivo using a zebrafish model. MTT assay and the scratch wound healing assay were performed on the osteosarcoma cell line (MG-63) to analyze the cytotoxic effect and antimigrative ability of noscapine, respectively. We also observed the antiangiogenic ability of noscapine on zebrafish embryos by analyzing the blood vessels namely the dorsal aorta, and intersegmental vessels development at 24, 48, and 72 h postfertilization. Real-time polymerase chain reaction was used to analyze the hypoxia signaling molecules' gene expression in MG-63 cells and zebrafish embryos. The findings from the scratch wound healing demonstrated that noscapine stopped MG-63 cancer cells from migrating under both hypoxia and normoxia. Blood vessel development and the heart rate in zebrafish embryos were significantly reduced by noscapine under both hypoxia and normoxia which showed the hemodynamics impact of noscapine. Noscapine also downregulated the cobalt chloride (CoCl₂) induced hypoxic signaling molecules' gene expression in MG-63 cells and zebrafish embryos. Therefore, noscapine may prevent MG-63 cancer cells from proliferating and migrating, as well as decrease the formation of new vessels and the production of growth factors linked to angiogenesis in vivo under both normoxic and hypoxic conditions.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140844725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Susceptibility of Leishmania to novel pentavalent organometallics: Investigating impact on DNA and membrane integrity in antimony(III)-sensitive and -resistant strains","authors":"Arshad Islam,&nbsp;Bruno Rodrigues do Prado,&nbsp;Dalton Dittz,&nbsp;Bernardo Lages Rodrigues,&nbsp;Sydnei Magno da Silva,&nbsp;Rubens L. do Monte-Neto,&nbsp;Muhammad Shabeer,&nbsp;Frédéric Frézard,&nbsp;Cynthia Demicheli","doi":"10.1002/ddr.22194","DOIUrl":"https://doi.org/10.1002/ddr.22194","url":null,"abstract":"<p>The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)-sensitive and -resistant <i>Leishmania</i> strains and toxicity in mammalian peritoneal macrophages. Ph₃M(L)₂ type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3-(dimethylamino)benzoic acid or 2-acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against <i>Leishmania amazonensis</i> and <i>L. infantum</i> but only the later ones demonstrated biocompatibility. Ph₃Sb(L1)₂ and Ph₃Bi(L1)₂ demonstrated distinct susceptibility profiles compared to inorganic Sb(III)-resistant strains of MRPA-overexpressing <i>L. amazonensis</i> and AQP1-mutated <i>L. guyanensis</i>. These complexes were able to permeate the cell membrane and interact with the <i>Leishmania</i> DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in <i>Leishmania</i> for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140844724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and bioactivity evaluation of clindamycin derivatives against multidrug-resistant bacterial strains","authors":"Yiduo Jia,&nbsp;Yinmeng Zhang,&nbsp;Hong Zhu,&nbsp;Ming Wang","doi":"10.1002/ddr.22182","DOIUrl":"https://doi.org/10.1002/ddr.22182","url":null,"abstract":"<p>Our research aims to reduce the bacterial resistance of clindamycin against Gram-positive bacteria and expand its range of bacterial susceptibility. First, we optimized the structure of clindamycin based on its structure–activity relationship. Second, we employed the fractional inhibitory concentration method to detect drugs suitable for combination with clindamycin derivatives. We then used a linker to connect the clindamycin derivatives with the identified combined therapy drugs. Finally, we tested antibacterial susceptibility testing and conducted in vitro bacterial inhibition activity assays to determine the compounds. with the highest efficacy. The results of our study show that we synthesized clindamycin propionate derivatives and clindamycin homo/heterodimer derivatives, which exhibited superior antibacterial activity compared to clindamycin and other antibiotics against both bacteria and fungi. In vitro bacteriostatic activity testing against four types of Gram-negative bacteria and one type of fungi revealed that all synthesized compounds had bacteriostatic effects at least 1000 times better than clindamycin and sulfonamides. The minimum inhibitory concentration (MIC) values for these compounds ranged from 0.25 to 0.0325 mM. Significantly, compound <b>5a</b> demonstrated the most potent inhibitory activity against three distinct bacterial strains, displaying MIC values spanning from 0.0625 to 0.0325 mM. Furthermore, our calculations indicate that compound <b>5a</b> is safe for cellular use. In conclusion, the synthesized compounds hold great promise in addressing bacterial antibiotic resistance.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140844723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of natural products and small-molecule therapeutics acting on central nervous system malignancies: Approaches for drug development, targeting pathways, clinical trials, and challenges","authors":"Ardalan Pasdaran,&nbsp;Irwin Darren Grice,&nbsp;Azadeh Hamedi","doi":"10.1002/ddr.22180","DOIUrl":"https://doi.org/10.1002/ddr.22180","url":null,"abstract":"<p>In 2021, the World Health Organization released the fifth edition of the central nervous system (CNS) tumor classification. This classification uses histopathology and molecular pathogenesis to group tumors into more biologically and molecularly defined entities. The prognosis of brain cancer, particularly malignant tumors, has remained poor worldwide, approximately 308,102 new cases of brain and other CNS tumors were diagnosed in the year 2020, with an estimated 251,329 deaths. The cost and time-consuming nature of studies to find new anticancer agents makes it necessary to have well-designed studies. In the present study, the pathways that can be targeted for drug development are discussed in detail. Some of the important cellular origins, signaling, and pathways involved in the efficacy of bioactive molecules against CNS tumorigenesis or progression, as well as prognosis and common approaches for treatment of different types of brain tumors, are reviewed. Moreover, different study tools, including cell lines, in vitro, in vivo, and clinical trial challenges, are discussed. In addition, in this article, natural products as one of the most important sources for finding new chemotherapeutics were reviewed and over 700 reported molecules with efficacy against CNS cancer cells are gathered and classified according to their structure. Based on the clinical trials that have been registered, very few of these natural or semi-synthetic derivatives have been studied in humans. The review can help researchers understand the involved mechanisms and design new goal-oriented studies for drug development against CNS malignancies.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140808168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors","authors":"Dana M. Odeh,&nbsp;Heba Abdelrasheed Allam,&nbsp;Fady Baselious,&nbsp;Walaa R. Mahmoud,&nbsp;Mohanad M. Odeh,&nbsp;Hany S. Ibrahim,&nbsp;Hatem A. Abdel-Aziz,&nbsp;Eman R. Mohammed","doi":"10.1002/ddr.22193","DOIUrl":"https://doi.org/10.1002/ddr.22193","url":null,"abstract":"<p>The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-<i>a</i>]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; <b>10d</b>, <b>10e</b>, <b>16a</b>, and <b>16c</b> based on cytotoxic studies. Compound <b>16a</b> revealed superior activity in the preliminary anticancer screening with GI % = 79.02–99.13 against 15 cancer cell lines at 10 μM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound <b>10d</b> revealed the best activity against CDK5/P25 (IC₅₀ = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound <b>16c</b> exhibited the highest inhibitory activity against CDK9/CYCLINT (IC₅₀ = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds <b>10e</b> and <b>16c</b> accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formulation characterization of lecithin organogel as topical drug delivery system for psoriasis: In-vitro permeation and preclinical evaluation","authors":"Prajakta Bule,&nbsp;Prashant Kadkanje,&nbsp;Ravikiran Kshirsagar,&nbsp;Eswara Rao Puppala,&nbsp;Vegi Ganga Modi Naidu,&nbsp;Naveen Chella","doi":"10.1002/ddr.22191","DOIUrl":"https://doi.org/10.1002/ddr.22191","url":null,"abstract":"<p>Psoriasis is a chronic inflammatory and proliferative skin disease that causes pathological skin changes and has a substantial impact on the quality of patient life. Apremilast was approved by the US Food and Drug Administration as an oral medication for psoriasis and is beneficial in mild to moderate conditions for chronic usage. However, 5%–7% of withdrawals were reported due to severe side effects. To address the issue, a localized drug delivery strategy via the topical route may be a viable approach. However, poor physicochemical properties make it vulnerable to passing through the skin, requiring a specialized drug delivery system to demonstrate its full potential via a topical route like lecithin organogel. The formulation was optimized by screening the suitable lecithin type and non-polar solvents based on the gel formation ability of lecithin and the solubility of apremilast in the solvent. The pseudo-ternary diagram was used to optimize the water content required to form the gel. The optimized gel was found to be shear thinning characterized for rheological parameters, in-vitro diffusion studies, and in-vitro skin distribution studies. Preclinical studies in Imiquimod-induced mice showed a better reduction in severity index, cytokine levels, and epidermal hyperplasia from the lecithin organogel group compared to the apremilast oral administration and marketed standard topical gel group. Based on these results, lecithin organogel can be considered a promising approach to deliver molecules like apremilast by topical route in psoriatic-like conditions.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitosan-coated nanoparticles in innovative cancer bio-medicine","authors":"Niloufar Rezaei,&nbsp;Ibrahim Zarkesh,&nbsp;Alireza Fotouhi,&nbsp;Hani Keshavarz Alikhani,&nbsp;Moustapha Hassan,&nbsp;Massoud Vosough","doi":"10.1002/ddr.22189","DOIUrl":"https://doi.org/10.1002/ddr.22189","url":null,"abstract":"<p>In the recent decade, nanoparticles (NPs) have had enormous implications in cancer biomedicine, including research, diagnosis, and therapy. However, their broad application still faces obstacles due to some practical limitations and requires further development. Recently, there has been more interest in the coated class of nanoparticles to address those challenges. Chitosan-coated NPs are simple to produce, biodegradable, biocompatible, exhibit antibacterial activity, and have less cytotoxicity. This study provides an updated and comprehensive overview of the application of chitosan-coated NPs as a promising class of NPs in cancer biomedicine. Additionally, we discussed chitosan-coated lipid, metal, and polymer-based nanoparticles in biomedical applications. Furthermore, different coating methods and production/characterization procedures were reviewed. Moreover, the biological and physicochemical advantages of chitosan-coated NPs, including facilitated controlled release, greater physicochemical stability, improved cell/tissue interaction, and enhanced bioavailability of medications, were highlighted. Finally, the prospects of chitosan-coated NPs in cancer biomedicine were discussed.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140808152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}