Project description:Immunoadjuvants are used to potentiate the activity of modern subunit vaccines that are based on molecular antigens. An emerging approach involves the combination of multiple adjuvants in a single formulation to achieve optimal vaccine efficacy. Herein, to investigate such potential synergies, we synthesized novel adjuvant conjugates based on the saponin natural product QS-21 and the aldehyde tucaresol via chemoselective acylation of an amine at the terminus of the acyl chain domain in QS saponin variants. In a preclinical mouse vaccination model, these QS saponin-tucaresol conjugates induced antibody responses similar to or slightly higher than those generated with related QS saponin variants lacking the tucaresol motif. The conjugates retained potent adjuvant activity, low toxicity, and improved activity-toxicity profiles relative to QS-21 itself and induced IgG subclass profiles similar to those of QS-21, indicative of both Th1 cellular and Th2 humoral immune responses. This study opens the door to installation of other substituents at the terminus of the acyl chain domain to develop additional QS saponin conjugates with desirable immunologic properties.
Project description:Aim of this work was to provide tamoxifen analogs with enhanced estrogen receptor (ER) binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known ER inhibitor ICI182,780. Theoretical calculations and molecular modeling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.
Project description:The glycoslated macrocyclic antibiotic fidaxomicin (1, tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of Clostridium difficile infections (CDI). Among the main limitations for this compound, its low water solubility impacts further clinical uses. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product. An increase in solubility of up to 25-fold with largely retained activity was observed. Furthermore, hybrid antibiotics were prepared that show improved antibiotic activities.
Project description:Three structurally defined QS-21-based immune adjuvant candidates (2a-2c) have been synthesized. Application of the two-stage activation glycosylation approach utilizing allyl glycoside building blocks improved the synthetic accessibility of the new adjuvants. The efficient synthesis and establishment of the stand-alone adjuvanticity of the examined synthetic adjuvant (2b) open the door to the pursuit of a new series of structurally defined QS-saponin-based synthetic adjuvants.
Project description:As a part of our project pointed at the search of new safe chemotherapeutic and chemoprophylactic agents against parasitic diseases, several compounds structurally related to 4-phenoxyphenoxyethyl thiocyanate (WC-9), which were modified at the terminal aromatic ring, were designed, synthesized and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas disease) and Toxoplasma gondii, the etiological agent of toxoplasmosis. Most of the synthetic analogs exhibited similar antiparasitic activity being slightly more potent than the reference compound WC-9. For example, the nitro derivative 13 showed an ED₅₀ value of 5.2 μM. Interestingly, the regioisomer of WC-9, compound 36 showed similar inhibitory action than WC-9 indicating that para-phenyl substitution pattern is not necessarily required for biological activity. The biological evaluation against T. gondii was also very promising. The ED₅₀ values corresponding for 13, 36 and 37 were at the very low micromolar level against tachyzoites of T. gondii.
Project description:Jahanyne, a lipopeptide with a unique terminal alkynyl and OEP (2-(1-oxo-ethyl)-pyrrolidine) moiety, exhibits anticancer activity. We synthesized jahanyne and analogs modified at the OEP moiety, employing an α-fluoromethyl ketone (FMK) strategy. Preliminary bioassays indicated that compound 1b (FMK-jahanyne) exhibited decreased activities to varying degrees against most of the cancer cells tested, whereas the introduction of a fluorine atom to the α-position of a hydroxyl group (2b) enhanced activities against all lung cancer cells. Moreover, jahanyne and 2b could induce G0/G1 cell cycle arrest in a concentration-dependent manner.
Project description:Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1' and P2', to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2' substitution was found to be effective, as seen in 5aa (1.54 nM), 5ad (0.71 nM), 5ac (0.31 nM), 5ae (0.28 nM), and 5af (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly 5ae, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2' subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.
Project description:SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The Mpro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 MPro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties.
Project description:QS-21 is one of the most promising new adjuvants for immune response potentiation and dose-sparing in vaccine therapy given its exceedingly high level of potency and its favorable toxicity profile. Melanoma, breast cancer, small cell lung cancer, prostate cancer, HIV-1, and malaria are among the numerous maladies targeted in more than 80 recent and ongoing vaccine therapy clinical trials involving QS-21 as a critical adjuvant component for immune response augmentation. QS-21 is a natural product immunostimulatory adjuvant, eliciting both T-cell- and antibody-mediated immune responses with microgram doses. Herein is reported the synthesis of QS-21A(api) in a highly modular strategy, applying novel glycosylation methodologies to a convergent construction of the potent saponin immunostimulant. The chemical synthesis of QS-21 offers unique opportunities to probe its mode of biological action through the preparation of otherwise unattainable nonnatural saponin analogues.