growth inhibitory
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2022 ◽  
Author(s):  
Rania M. Gomaa ◽  
Magda A. El-Sayed ◽  
Khalid Bashir Selim

Abstract New compounds of 4-anilino-6-substituted quinazoline were designed, synthesized and tested for their EGFR-TK and tumor growth inhibitory activities. The synthesized compounds were appended with amides 6 and 7, dithiocarbamate ester 8a–f or urea/thiourea 9–12 moieties at C-6 of the quinazoline ring to work as extra hydrogen bond acceptors. All the synthesized compounds were effective against EGFR-TK activity, particularly, derivatives 8a, 8f and 9 with IC50 values of 0.14±0.003, 0.119±0.003, and 0.115±0.002 μM, respectively, showed the best activities. The three compounds were further assayed for their cytotoxicity against MCF-7, H-69, SKOV-3 and LS-174T cell lines. Multikinase enzymes inhibition activity of compound 9 was further screened including VEGFR-2, c-MER, c-MET and Her-2. Compounds 8a, 8f, and 9 were docked into the ATP binding site of EGFR-TK which also had resemblance binding pattern to erlotinib with extra binding mode with Cys-773 at the gatekeeper of the enzyme. Cell cycle analyses of MCF-7 cells treated with 8a and 9 was measured in addition to other related factors such as Bax, Bcl-2, caspase-9, and PARP-1.


Biocelebes ◽  
2022 ◽  
Vol 15 (2) ◽  
pp. 90-97
Author(s):  
Gaby Maulida Nurdin

This study aimed to determine the effect of concentration ethanol extract from tembelakan leaf (Lantana camara Linn)  on bacteria growth of Staphylococcus aureus and Escherichia coli. Extraction was done by maceration using ethanol 96% and then separated using rotary evaporator. Antibacterial activity test of the ethanol extract by Well agar diffusion method. Variation in crude extract saponin used in this study was 5%, 10%, 15%, 20%, 25% and positive controls were used for comparison with Amoxicilin and Chloramphenicole concentration of 25 µg/mL and DMSO as a negative control. The results of antibacterial activity test is indicated by the formation of growth inhibitory region S. aureus and E. coli. The result of growth inhibitory regions was analyzed by One way ANOVA. One way ANOVA test results indicate that there are effects of ethanol extract concentration of tembelekan leaf (L. camara Linn) against S. aureus and E. coli. Effective concentration of ethanol extract tembelekan leaf (L. camara Linn) when compared with positive control to inhibit the growth of S. aureus and E. coli is at 25% with a relatively strong antibacterial activity. Test with phytochemicals screening method which is showed that tembelekan leaf contains the flavanoid, saponins, and tannins compounds as antibacterial


Author(s):  
Yoichi Morofuji ◽  
Shinsuke Nakagawa ◽  
Kenta Ujifuku ◽  
Takashi Fujimoto ◽  
Kaishi Otsuka ◽  
...  

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering.’


Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 88
Author(s):  
Lital Cohen ◽  
Yehuda G. Assaraf ◽  
Yoav D. Livney

Prostate cancer (PC) is the most common cancer in men over 50 and the 4th most prevalent human malignancy. PC treatment may include surgery, androgen deprivation therapy, chemotherapy, and radiation therapy. However, the therapeutic efficacy of systemic chemotherapy is limited due to low drug solubility and insufficient tumor specificity, inflicting toxic side effects and frequently provoking the emergence of drug resistance. Towards the efficacious treatment of PC, we herein developed novel selectively PC-targeted nanoparticles (NPs) harboring a cytotoxic drug cargo. This delivery system is based upon PEGylated nanostructured lipid carriers (NLCs), decorated with a selective ligand, targeted to prostate-specific membrane antigen (PSMA). NPs loaded with cabazitaxel (CTX) displayed a remarkable loading capacity of 168 ± 3 mg drug/g SA-PEG, encapsulation efficiency of 67 ± 1%, and an average diameter of 159 ± 3 nm. The time-course of in vitro drug release from NPs revealed a substantial drug retention profile compared to the unencapsulated drug. These NPs were selectively internalized into target PC cells overexpressing PSMA, and displayed a dose-dependent growth inhibition compared to cells devoid of the PSMA receptor. Remarkably, these targeted NPs exhibited growth-inhibitory activity at pM CTX concentrations, being markedly more potent than the free drug. This selectively targeted nano-delivery platform bears the promise of enhanced efficacy and minimal untoward toxicity.


2021 ◽  
Author(s):  
Zahra Sadeghian ◽  
Mohammad Bayat ◽  
Fatemeh Safari

Abstract Chemotherapy is one of the most common types of treatment among cancer patients and by using potent chemicals and agents, tumor promotion was inhibited. Despite the usage of many chemical agents in cancer therapy, cancer is still incurable. It seems that the synthesis of new compounds with high efficiency on cancer cells and low side effects on normal cells will remain a critical challenge among researchers in this area. In the present work, a fast and straightforward process for the transformations involving tryptanthrins, malononitrile, some types of CH-acids such as 1,3-cyclohexanedione, dimedone, and 4-hydroxycumarin resulting in preparing spiro[chromene-indolo[2,1-b]quinazoline] and spiro[indolo[2,1-b]quinazoline-pyrano[3,2-c]chromene] derivatives through sequential Knoevenagel/Michael/intramolecular cyclization sequences was reported. at room temperature. This protocol benefits some notable advantages including short reaction time, mild reaction condition, and simple purification, which make it interesting. Furthermore, it was carried out at room temperature, so it is according to green chemistry procedures. Also, antitumor screening of our new synthetic compounds (4a-i) was evaluated on pancreatic cancer cells (Panc1), breast cancer cells (MDA-MB-231), prostate cancer cells (PC3), and normal human adult dermal fibroblast cells (HDF) by using MTT assay using etoposide as a positive control. We found that 50% growth inhibitory concentration (IC50) values of our synthetic compounds were not lower than etoposide against three cancer cell lines.


Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 14
Author(s):  
Victoria Chamberlain ◽  
Yvette Drew ◽  
John Lunec

As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 inhibitors. Growth inhibition and cytotoxic assays were used to evaluate uLMS cell line responses to MDM2 inhibitors as single agents and in combination, qRT-PCR to assess transcriptional changes and Caspase-Glo 3/7 assay to detect apoptosis. RG7388 and HDM201 are potent, selective antagonists of the MDM2-p53 interaction that can effectively stabilise and activate p53 in a dose-dependent manner. GSK2830371, a potent and selective WIP1 phosphatase inhibitor, was shown to significantly potentiate the growth inhibitory effects of RG7388 and HDM201, and significantly increase the mRNA expression of p53 transcriptional target genes in a p53WT cell line at a concentration that has no growth inhibitory effects as a single agent. RG7388, HDM201 and GSK2830371 failed to induce apoptosis as single agents; however, a combination treatment tipped cells into apoptosis from senescence. These data present the possibility of MDM2 and WIP1 inhibitor combinations as a potential treatment option for p53WT uLMS patients that warrants further investigation.


2021 ◽  
Vol 14 (1) ◽  
pp. 189-192
Author(s):  
A.L. Yusuf ◽  
B. Abdullahi ◽  
I. Abdulaziz

Phytochemical and antimicrobial activity of methanol extract of Albizia ferruginea (Guill and Perr) which belongs to the family of Fabaceae were studied. Phytochemical studies on the plant leaves showed that they contained alkaloids, tannins, flavonoids, steroids, saponins, cardiac glycoside and carbohydrate. Methanol extract of Albizia ferruginea showed growth inhibitory effects of varying degrees on S. feacalis, S. typhi, S. paratyphi, Shigella dysentriae and Klebsiella pneumonia but was not active on Streptococcus pyogenes and Pseudomonas aeruginosa. The minimum inhibitory concentration (MIC) of the extract was determined for the organisms whose growths were inhibited. The extract had MIC of 3.25mg/ml for S. feacalis, S. paratyphi, S. dysentriae and K. pneumoniae respectively. The antimicrobial studies of the extracts really justify the numerous folkloric uses of the plant parts in the treatment of some common ailments such as diarrhea, dysentery, fever, cough, pain and skin infections.


2021 ◽  
Vol 14 (12) ◽  
pp. 1318
Author(s):  
Nitin T. Telang ◽  
Hareesh B. Nair ◽  
George Y. C. Wong

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated with systemic toxicity, spontaneous and/or acquired tumor resistance and the emergence a of drug-resistant stem cell population. These limitations lead to advanced stage metastatic cancer. Current emphasis is on research directions that identify efficacious, naturally occurring agents representing an unmet need for testable therapeutic alternatives for therapy resistant breast cancer. Chinese herbs are widely used in traditional Chinese medicine in women for estrogen related health issues and also for integrative support for cancer treatment. This review discusses published evidence on a TNBC model for growth inhibitory effects of several mechanistically distinct nontoxic Chinese herbs, most of them nutritional in nature, and identifies susceptible pathways and potential molecular targets for their efficacy. Documented anti-proliferative and pro-apoptotic effects of these herbs are associated with downregulation of RB, RAS, PI3K, and AKT signaling, modulation of Bcl-2/BAX protein expressions and increased caspase activity. This review provides a proof of concept for Chinese herbs as testable alternatives for prevention/therapy of TNBC.


2021 ◽  
Author(s):  
◽  
Hemi Cumming

<p>Pateamine A (14) is a natural product that was extracted from a marine sponge off the coast of the South Island of New Zealand. It exhibits potent biological activity, mediated by a number of protein targets. The most sensitive of these towards pateamine are the eIF4A isoforms, which have roles in translation of RNA into proteins and in nonsensemediated decay. The inhibition of these enzymes may be beneficial in the treatment of cancer or certain types of genetic diseases. Unfortunately, the naturally available supply of pateamine is very limited and its total synthesis is complex. This provides an imperative for the design of a synthetic strategy that would allow the preparation of simplified analogues of pateamine to gain further insight into the necessary features for activity and selectivity of the eIF4A isoforms. Based on the principles of pharmacophore modification, chemical synthesis and the structure-activity relationships (SARs) reported by Romo and co-workers, a simplified analogue of pateamine, 107, was targeted that lacked a number of pendant methyl groups and contained a triazole in place of the thiazole. Synthesis of the target analogue 107 was achieved through preparation of four fragments, followed by an investigation of suitable coupling reactions and the optimal order of connectivity. This included the preparation of two macrocycles that lacked the trienecontaining sidechain, and of simplified model substrates that allowed investigation of two olefination reactions (namely, the Wittig and Julia-Kocienski reactions) for the attachment of the sidechain fragment. After substantial optimisation of the fragment preparation and connectivity, the complete synthesis of the target pateamine analogue 107 was achieved. The synthesis features: 1) a Julia Kocienski olefination between a highly functionalised three-carbon sulfone and a conjugated aldehyde to attach the sidechain; 2) copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction to form the triazole; 3) ring opening of a δ-substituted α,β-unsaturated lactone to access the Z,E-dienoate moiety; and 4) Yamaguchi macrolactonisation. This synthesis represents a convergent strategy with 11 steps in the longest linear sequence, which utilises easily accessible starting materials (i.e. furan (or cis-butenediol), epichlorohydrin, ε-caprolactone and 1,3-propanediol) and reagents. The approach is also broadly applicable to the preparation of a range of analogue variants. The simplified analogue (107) was found to have significantly lower activity, in comparison to pateamine A (14), in a growth inhibitory assay. Presuming this loss of bioactivity is at least partially caused by the incorporation of the triazole (in place of the thiazole), this raises an interesting question as to the role of the thiazole moiety in the bioactivity of pateamine A. The adaptation of the synthetic strategy devised in this thesis to the preparation of future analogues will enable study of the mechanism of action of pateamine and related compounds, and probe the requirements for effective binding to the eIF4A isoforms.</p>


2021 ◽  
Author(s):  
◽  
Hemi Cumming

<p>Pateamine A (14) is a natural product that was extracted from a marine sponge off the coast of the South Island of New Zealand. It exhibits potent biological activity, mediated by a number of protein targets. The most sensitive of these towards pateamine are the eIF4A isoforms, which have roles in translation of RNA into proteins and in nonsensemediated decay. The inhibition of these enzymes may be beneficial in the treatment of cancer or certain types of genetic diseases. Unfortunately, the naturally available supply of pateamine is very limited and its total synthesis is complex. This provides an imperative for the design of a synthetic strategy that would allow the preparation of simplified analogues of pateamine to gain further insight into the necessary features for activity and selectivity of the eIF4A isoforms. Based on the principles of pharmacophore modification, chemical synthesis and the structure-activity relationships (SARs) reported by Romo and co-workers, a simplified analogue of pateamine, 107, was targeted that lacked a number of pendant methyl groups and contained a triazole in place of the thiazole. Synthesis of the target analogue 107 was achieved through preparation of four fragments, followed by an investigation of suitable coupling reactions and the optimal order of connectivity. This included the preparation of two macrocycles that lacked the trienecontaining sidechain, and of simplified model substrates that allowed investigation of two olefination reactions (namely, the Wittig and Julia-Kocienski reactions) for the attachment of the sidechain fragment. After substantial optimisation of the fragment preparation and connectivity, the complete synthesis of the target pateamine analogue 107 was achieved. The synthesis features: 1) a Julia Kocienski olefination between a highly functionalised three-carbon sulfone and a conjugated aldehyde to attach the sidechain; 2) copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction to form the triazole; 3) ring opening of a δ-substituted α,β-unsaturated lactone to access the Z,E-dienoate moiety; and 4) Yamaguchi macrolactonisation. This synthesis represents a convergent strategy with 11 steps in the longest linear sequence, which utilises easily accessible starting materials (i.e. furan (or cis-butenediol), epichlorohydrin, ε-caprolactone and 1,3-propanediol) and reagents. The approach is also broadly applicable to the preparation of a range of analogue variants. The simplified analogue (107) was found to have significantly lower activity, in comparison to pateamine A (14), in a growth inhibitory assay. Presuming this loss of bioactivity is at least partially caused by the incorporation of the triazole (in place of the thiazole), this raises an interesting question as to the role of the thiazole moiety in the bioactivity of pateamine A. The adaptation of the synthetic strategy devised in this thesis to the preparation of future analogues will enable study of the mechanism of action of pateamine and related compounds, and probe the requirements for effective binding to the eIF4A isoforms.</p>


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