scholarly journals Synthesis and Antiproliferative Activities of Conjugates of Paclitaxel and Camptothecin with a Cyclic Cell-Penetrating Peptide

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1427 ◽  
Author(s):  
Naglaa Salem El-Sayed ◽  
Amir Nasrolahi Shirazi ◽  
Muhammad Imran Sajid ◽  
Shang Eun Park ◽  
Keykavous Parang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Water Solubility ◽  
Cyclic Peptide ◽  
Solid Phase ◽  
Parent Drug ◽  
Hydroxyl Group ◽  
Esterification Reaction ◽  
Cell Penetrating Peptide ◽  
Cell Penetrating ◽  
Mcf 7

Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C2′ hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(βAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through a formyl linker affording two different conjugates, namely CPT1 and CPT2. All the conjugates showed better water solubility as compared to the parent drug. The cytotoxicity assay of the drugs and their conjugates with the peptides were evaluated in the human breast cancer MCF-7 cell line. PTX inhibited cell proliferation by 39% while the PTX-peptide conjugate inhibited the proliferation by ~18% after 72 h incubation. On the other hand, CPT, CPT1, and CPT2 reduced the cell proliferation by 68%, 39%, and 62%, respectively, in the MCF-7 cell lines at 5 µM concentration after 72 h incubation.

scholarly journals Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity

2020 ◽  
Vol 22 (1) ◽  
pp. 242
Author(s):  
Sara Silva ◽  
Cláudia Alves ◽  
Diana Duarte ◽  
Ana Costa ◽  
Bruno Sarmento ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Drug Repurposing ◽  
Parent Drug ◽  
Ache Inhibitor ◽  
Amphipathic Peptide ◽  
Reference Drug ◽  
Mcf 7

Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.

scholarly journals Pharmacodynamics of siRNARANKL and Oestrogen Loaded MSNs-CADY on Human Periodontal Ligament Stem Cells with Porphyromonas gingivalis infection

2020 ◽  
Author(s):  
Liang Song ◽  
Xiaojun Shi ◽  
Fengling Hu ◽  
Huijuan Chen ◽  
Bin Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Drug Release ◽  
Mesoporous Silica ◽  
Porphyromonas Gingivalis ◽  
Periodontal Ligament ◽  
Mesoporous Silica Nanoparticles ◽  
Cell Penetrating Peptide ◽  
Periodontal Ligament Stem Cells ◽  
Cell Penetrating

Abstract Background: Periodontitis irreversibly invades and destroys periodontal supporting tissues, loses the ability of periodontal regeneration and restoration, and eventually leads to tooth loosening and loss. periodontal ligament stem cells (PDLSCs) hold great promises for periodontal tissue regeneration which was the potential target of periodontitis treatment, siRNARANKL and oestrogen can help PDLSCs maintain normal function, however, it was very difficult for siRNARANKL and oestrogen to get into PDLSCs. Here, Cell penetrating peptide CADY was modified on the surface of siRNARANKL and oestrogen loaded mesoporous silica nanoparticles (MSNs) to carry them into Porphyromonas gingivalis infected PDLSCs, Then further affect the proliferation of PDLSCs. Methods: 120-150 nm Mesoporous silica nanoparticles (MSNs) was prepared, and the biocompatibility, loading capacity and drug release properity were tested; MSNs was modified by penetrating peptide CADY and the prepared MSNs/CADY was loaded with siRNARANKL and oestrogen; In vitro drug release of siRNARANKL/MSNs-CADY and oestrogen/MSNs-CADY was tested by using semi-permeable dialysis bag diffusion; Cellular uptake and internalization of FITC-Labeled MSNs and FITC-Labeled MSNs-CADY was observed by use of Laser confocal microscopy; Finally, the effect of siRNARANKL and oestrogen loaded MSNs-CADY on cell proliferation of Porphyromonas gingivalis infected human periodontal ligament stem cells was tested by MTT assay. Results: according to the results, MSNs-CADY with a concentration of 6.25-200 ug/mL have no toxic to PDLSCs; 24.6 mg oestrogen and 0.5 mM siRNARANKL can be loaded into 1mg of MSNs-CADY; and drug loaded MSNs-CADY nanodrug carriers can release siRNARANKL and oestrogen stably for at least 48 h; After modification with cell penetrating peptide CADY, more MSNs-CADY can be taken by PDLSCs. siRNARANKL/oestrogen/MSNs-CADY can increase the proliferation of PDLSCs significantly. Conclusion: siRNARANKL/oestrogen/MSNs-CADY constructed can significantly improve the cell proliferation of P-gingivalis infected PDLSCs, this nano drug carrier has the potential to be used in PDLSCs -based periodontitis treatment, this work provided a useful theoretical basis and therapeutic ideas for the treatment of periodontitis.

scholarly journals [(WR)8WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 301
Author(s):  
Khalid Zoghebi ◽  
Hamidreza Montazeri Aliabadi ◽  
Rakesh Kumar Tiwari ◽  
Keykavous Parang
Keyword(s):  
Cell Viability ◽  
Cyclic Peptide ◽  
Acquired Resistance ◽  
Parent Drug ◽  
Physical Mixture ◽  
Multi Drug Resistance ◽  
Ovarian Adenocarcinoma ◽  
Arginine Residues ◽  
The Stability ◽  
Mcf 7

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]9 containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)8WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the corresponding physical mixture of the peptide and Dox to evaluate the effectiveness of synthesized conjugate compared to the parent drug alone. [(WR)8WKβA]-Dox conjugate showed higher antiproliferative activity at 10 µM and 5 µM than Dox alone at 5 μM. The conjugate inhibited the cell viability of ovarian adenocarcinoma (SK-OV-3) by 59% and the triple-negative breast cancer cells MDA-MB-231 and MCF-7 by 71% and 77%, respectively, at a concentration of 5 μM after 72 h of incubation. In contrast, Dox inhibited the proliferation of SK-OV-3, MDA-MB-231, and MCF-7 by 35%, 63%, and 57%, respectively. Furthermore, [(WR)8WKβA]-Dox conjugate (5 µM) inhibited the cell viability of Dox-resistant cells (MES-SA/MX2) by 92%, while the viability of cells incubated with free Dox was only 15% at 5 μM. Confocal microscopy images confirmed the ability of both Dox conjugate and the physical mixture of the peptide with the drug to deliver Dox through an endocytosis-independent pathway, as the uptake was not inhibited in the presence of endocytosis inhibitors. The stability of Dox conjugate was observed at different time intervals using analytical HPLC when the conjugate was incubated with 25% human serum. Half-life (t1/2) for [(WR)8WKβA]-Dox conjugate was (∼6 h), and more than 80% of the conjugate was degraded at 12 h. The release of free Dox was assessed intracellularly using the CCRF-CEM cell line. The experiment demonstrated that approximately 100% of free Dox was released from the conjugate intracellularly within 72 h. These data confirm the ability of the cyclic cell-penetrating peptide containing tryptophan and arginine residues as an efficient tool for delivery of Dox and for overcoming resistance to it.

scholarly journals Cell-penetrating peptide-conjugated XIAP-inhibitory cyclic hexapeptides enter into Jurkat cells and inhibit cell proliferation

FEBS Journal ◽  
2008 ◽  
Vol 275 (23) ◽  
pp. 6011-6021 ◽  
Author(s):  
Yusuke Sasaki ◽  
Motoko Minamizawa ◽  
Akihiro Ambo ◽  
Shigeki Sugawara ◽  
Yukiko Ogawa ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Jurkat Cells ◽  
Cell Penetrating Peptide ◽  
Cell Penetrating ◽  
Cyclic Hexapeptides ◽  
Inhibit Cell Proliferation

scholarly journals 3-O-Carbamoyl-5,7,20-O-trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6421
Author(s):  
Sitong Wu ◽  
Guanglin Chen ◽  
Qiang Zhang ◽  
Guangdi Wang ◽  
Qiao-Hong Chen
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Water Solubility ◽  
Prostate Cancer Cell ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Alcoholic Hydroxyl

To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure–activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2–C3, providing an avenue for achieving 3-O-carbamoyl-5,7,20-O-trimethylsilybins. The application of the synthetic method can be extended to the synthesis of 3-O-carbamoyl-3′,4′,5,7-O-tetramethyltaxifolins. The antiproliferative potency of 5,7,20-O-trimethylsilybin and its nine 3-carbamoyl derivatives were assessed in an AR-positive LNCaP prostate cancer cell line and two AR-null prostate cancer cell lines (PC-3 and DU145). Our preliminary bioassay data imply that 5,7,20-O-trimethylsilybin and four 3-O-carbamoyl-5,7,20-O-trimethylsilybins emerge as very promising lead compounds due to the fact that they can selectively suppress AR-positive LNCaP cell proliferation. The IC50 values of these five 5,7,20-O-trimethylsilybins against the LNCaP cells fall into the range of 0.11–0.83 µM, which exhibit up to 660 times greater in vitro antiproliferative potency than silibinin. Our findings suggest that carbamoylated 5,7,20-O-trimethylsilybins could serve as a natural product-based scaffold for new antiandrogens for lethal castration-resistant prostate cancer.

scholarly journals Cycloartane and Stigmastane Type Triterpenoids from Pothos scandens Inhibit Estradiol (E2) Induced Proliferations in Breast Cancer Cells

2019 ◽  
Vol 18 (1) ◽  
pp. 93-102
Author(s):  
Md Abdul Muhit ◽  
Kaoru Umehara ◽  
Nahid Sharmin ◽  
Hiroshi Noguchi
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
T47d Cell ◽  
Spectroscopic Studies ◽  
Hydroxyl Group ◽  
Breast Cancer Cell Lines ◽  
Chromatographic Technique ◽  
Antiestrogenic Activity ◽  
Mcf 7

Four cycloartane type triterpenoids and three stigmastane type steroids were isolated from the methanolic extract of stem and root part of Pothos scandens L. (Araceae), a Bangladeshi medicinal plant by high performance liquid chromatographic technique. The compounds were characterized as 24-methylenecycloartanol (1), 24-methylenecycloartenone (2), 24-en-cycloartenone (3), 24-methylenecycloartanyl ferulate (4), stigmast-4-en-3-one (5), stigmast-4,22-diene-3-one (6) and β-sitosterol glucoside (7) through extensive 1D and 2D NMR spectroscopic studies. All the isolates were evaluated for their estrogenic/antiestrogenic activity using the estrogen-responsive breast cancer cell lines, MCF-7 and T47D. The results showed that all the compounds possess mild to strong antiestrogenic activity in both cell lines which was compared to positive control tamoxifen. 24- Methylenecycloartanol (1), which contains a hydroxyl group in its C-3 position, inhibited 90% of estradiol (E2)- induced cell proliferation in MCF-7 and T47D cell lines at a concentration of 0.01 μM only. 24- Methylenecycloartanyl ferulate (4) and stigmast-4,22-diene-3-one (6) showed 90% of estradiol (E2)-induced cell proliferation in T47D cell only at a concentration of 0.01 μM whereas 10.0 μM was required for 24- methylenecycloartanyl ferulate (4) for the same activity in MCF-7 cells. This is the first report of isolation of these compounds from the plant along with their antiestrogenic property. Dhaka Univ. J. Pharm. Sci. 18(1): 93-102, 2019 (June)

scholarly journals Coupling the cell-penetrating peptides transportan and transportan 10 to primaquine enhances its activity against liver-stage malaria parasites

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 221-226 ◽  
Author(s):  
Luísa Aguiar ◽  
Marta Machado ◽  
Margarida Sanches-Vaz ◽  
Miguel Prudêncio ◽  
Nuno Vale ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Parent Drug ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
Malaria Parasites ◽  
Peptide Conjugates ◽  
Liver Stage ◽  
Cell Penetrating

Novel primaquine–cell penetrating peptide conjugates were synthesised and testedin vitroagainst liver stagePlasmodium bergheiparasites, showing that generally the conjugates were more active than the parent peptides and, in some cases, than the parent drug.

Co-delivery of drug nanoparticles and siRNA mediated by a modified cell penetrating peptide for inhibiting cancer cell proliferation

RSC Advances ◽  
2015 ◽  
Vol 5 (26) ◽  
pp. 20554-20556 ◽  
Author(s):  
Dafeng Chu ◽  
Wen Xu ◽  
Ran Pan ◽  
P. Chen
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Cancer Cell ◽  
Cell Penetrating Peptide ◽  
Cancer Cell Proliferation ◽  
Cancer Cell Growth ◽  
Drug Nanoparticles ◽  
Cell Penetrating

Modified cell penetrating peptide can stabilize drug nanoparticles with improved efficacy and co-deliver siRNA inducing synergy on the inhibition of cancer cell growth.

Sign in / Sign up

Export Citation Format

Share Document