Computer-aided drug design (CADD) often involves virtual screening (VS) of large compound datasets and the availability of such is vital for drug discovery protocols. We assess the bioactivity and “drug-likeness” of a relatively small but structurally diverse dataset (containing >1,000 compounds) from African medicinal plants, which have been tested and proven a wide range of biological activities. The geographical regions of collection of the medicinal plants cover the entire continent of Africa, based on data from literature sources and information from traditional healers. For each isolated compound, the three dimensional (3D) structure has been used to calculate physico-chemical properties used in the prediction of oral bioavailability on the basis of Lipinski’s “Rule of Five”. A comparative analysis has been carried out with the “drug-like”, “lead-like”, and “fragment-like” subsets, as well as with the Dictionary of Natural Products. A diversity analysis has been carried out in comparison with the ChemBridge diverse database. Furthermore, descriptors related to absorption, distribution, metabolism, excretion and toxicity (ADMET) have been used to predict the pharmacokinetic profile of the compounds within the dataset. Our results prove that drug discovery, beginning with natural products from the African flora, could be highly promising. The 3D structures are available and could be useful for virtual screening and natural product lead generation programs.
A series of p-terphenyl-based macrocycles, containing highly distorted p-phenylene units, have been synthesized. Biaryl bonds of the nonplanar p-terphenyl nuclei were constructed in the absence of Pd-catalyzed or Ni-mediated cross-coupling reactions, using 1,4-diketones as surrogates to strained arene units. A streamlined synthetic protocol for the synthesis of 1,4-diketo macrocycles has been developed, using only 2.5 mol % of the Hoveyda-Grubbs second-generation catalyst in both metathesis and transfer hydrogenation reactions. Under protic acid-mediated dehydrative aromatization conditions, the central and most strained benzene ring of the p-terphenyl systems was susceptible to rearrangement reactions. To overcome this, a dehydrative aromatization protocol using the Burgess reagent was developed. Under these conditions, no strain-induced rearrangement reactions occur, delivering p-phenylene units with up to 28.4 kcal/mol strain energy and deformation angles that sum up to 40°.
A new synthetic strategy that employs a relatively unstrained, 1,4-diketo-bridged macrocycle as a precursor to a strained, 1,4-arene-bridged (bent para-phenylene) macrocycle has been developed. The distorted p-terphenyl nucleus (CPP fragment) of the macrocycle has been characterized by X-ray crystallography, and a direct, regioselective bromination protocol of the macrocyclic system is reported.
The synthesis of 1,2,4,5- and 1,2,9,10-tetrasubstituted and 1,2,4,5,8-pentasubsutituted pyrenes has been achieved by initially functionalizing the K-region of pyrene. Bromination, acylation, and formylation reactions afford high to moderate levels of regioselectivity, which facilitate the controlled introduction of other functional groups about 4,5-dimethoxypyrene. Access to 4,5-dimethoxypyren-1-ol and 9,10-dimethoxypyren-1-ol enabled a rare, C-2 primary alkyl substitution of pyrene.
Protein
aggregation is an obstacle for the development of new biopharmaceuticals,
presenting challenges in shipping and storage of vital therapies.
Though a variety of materials and methods have been explored, the
need remains for a simple material that is biodegradable, nontoxic,
and highly efficient at stabilizing protein therapeutics. In this
work, we investigated zwitterionic polypeptides prepared using a rapid
and scalable polymerization technique and conjugated to a supramolecular
macrocycle host, cucurbit[7]uril, for the ability to inhibit aggregation
of model protein therapeutics insulin and calcitonin. The polypeptides
are based on the natural amino acid methionine, and zwitterion sulfonium
modifications were compared to analogous cationic and neutral structures.
Each polymer was end-modified with a single cucurbit[7]uril macrocycle
to afford supramolecular recognition and binding to terminal aromatic
amino acids on proteins. Only conjugates prepared from zwitterionic
structures of sufficient chain lengths were efficient inhibitors of
insulin aggregation and could also inhibit aggregation of calcitonin.
This polypeptide exhibited no cytotoxicity in human cells even at
concentrations that were five-fold of the intended therapeutic regime.
We explored treatment of the zwitterionic polypeptides with a panel
of natural proteases and found steady biodegradation as expected,
supporting eventual clearance when used as a protein formulation additive.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.