Background: The medicinally active plant Oroxylum indicum (OI) has drawn considerable research interest because of itsmany observed biological activities. Of particular interest is its antitumorigenic activity. The plant is a rich source of flavonoids and theirglycosides. Recently flavonoids have been described as inhibitors of kexin-type proteases of superfamily Proprotein Convertase Subtilisin/Kexins (PCSKs) which have been implicated in tumor growth and malignancy. These enzymes particularly furin (PCSK3) cleavesinactive precursor growth factors into their mature forms that promote tumor growth. As a result, finding furin-inhibitors became of highinterest in cancer research. In this regard, the plant OI with known anticancer activities may provide an important source. Objective: Theobjective of this study is to examine and compare anti-tumorigenic activity of furin inhibitory flavonoid compounds from OI. Results:Studies were conducted to evaluate the effect on CT-26 cell proliferation and migration of 4 flavonoids baicalein, chrysin, oroxylin-Aand its glycoside isolated from OI. Data revealed that baicalein exhibited most potent inhibitory effect on proliferation and migration onthe analyzed tumor cell line. Baicalein at 10 μM completely blocked the proliferation even after 5 days. The results are consistent withthe observed in vitro anti-furin activity of baicalein as measured against a fluorogenic peptide and pro-hVEGF-C as substrates. MatureVEGF-C is a strong indicator and biomarker of tumor progression and therefore the antifurin activity may explain the observed anticancerproperties of baicalein. Since baicalein is the major constituent of OI, our data provided scientific rationale for the observed anticanceractivity of OI and also offered a new lead molecule for future exploration as potential antitumor agents.

Inhibition of Tumor Cells Proliferation and Migration by the Flavonoid Furin Inhibitor Isolated From Oroxylum indicum

COVID-19 pandemic is currently decimating the world's most advanced technologies and largest economies and making its way to the continent of Africa. Weak medical infrastructure and over-reliance on medical aids may eventually predict worse outcomes in Africa. To reverse this trend, Africa must re-evaluate the only area with strategic advantage; phytotherapy. One of the many plants with previous antiviral potency is against RNA viruses is Aframomum melegueta. In this study, one hundred (100) A. melegueta secondary metabolites have been mined and computational evaluated for inhibition of host furin, and SARS-COV-2 targets including 3C-like proteinase (Mpro /3CLpro ), 2'-O-ribose methyltransferase (nsp16) and surface glycoprotein/ACE2 receptor interface. Silica-gel column partitioning of A. melegueta fruit/seed resulted in 6 fractions tested against furin activity. Diarylheptanoid (Letestuianin A), phenylpropanoid (4-Cinnamoyl-3-hydroxy-spiro[furan-5,2'-(1'H)-indene]-1',2,3'(2'H,5H)-trione), flavonoids (Quercetin, Apigenin and Tectochrysin) have been identified as high-binding compounds to SARS-COV-2 targets in a polypharmacology manner. Di-ethyl-ether (IC50 = 0.03 mg/L), acetone (IC50 = 1.564 mg/L), ethyl-acetate (IC50 = 0.382 mg/L) and methanol (IC50 = 0.438 mg/L) fractions demonstrated the best inhibition in kinetic assay while DEF, ASF and MEF completely inhibited furin-recognition sequence containing Ebola virus-pre-glycoprotein. In conclusion, A. melegueta and its secondary metabolites have potential for addressing the therapeutic needs of African population during the COVID-19 pandemic.

Aframomum melegueta secondary metabolites exhibit polypharmacology against SARS-CoV-2 drug targets: in vitro validation of furin inhibition.

The review is devoted to the analysis of the relationship between a chemical structure and properties of low-molecular weight inhibitors of furin, the most studied proprotein convertase, which is involved in the development of some pathologies, such as oncologic diseases, viral and bacterial infections, etc. The latest data concerning the influence of peptides, pseudo-peptides, aromatic and heterocyclic compounds, some natural ones such as flavonoids, coumarins, and others on enzyme inactivation are considered. The power of furin inhibition is shown to rise with the increasing number of positively charged groups in the structure of these compounds. Peptidomimetics (Ki = 5-8 pM) are shown to be the most effective furin inhibitors. The synthesized substances, however, have not been used in practical application yet. Nowadays it is very important to find more selective inhibitors, improve their stability, bioavailability and safety for the human organism.

/pdf/chemical-structure-and-properties-of-low-molecular-furin-1lhtuemdhe.pdf

Chemical structure and properties of low-molecular furin inhibitors.

A series of novel non-peptidicfurin inhibitors with values of inhibitory constants (Ki) in the range of 0.74-1.54 μM was obtained by interactions of aminoguanidine hydrocarbonate with three diaryldicarbalde- hydes. Correspondingly p-hydroquinone, piperazine and adipic acid were used as linkers between their ben- zene moieties. Docking studies of these new inhibitors into recently published 3D-structure of human furin (PDB code 4OMC) showed that they were able to interact with subsites S1 and S4 of the enzyme. The overall arrangement of bisamidinohydrazones into furin active site was similar to the position of the ligand co- crystallized with a protease. Observations obtained with molecular modeling allowed further guidance into chemical modifications of the synthesized inhibitors which improve their inhibitory activity.

/pdf/synthesis-biological-evaluation-and-docking-of-novel-4lmhrtwor4.pdf

Synthesis, biological evaluation and docking of novel bisamidinohydrazones as non-peptide inhibitors of furin.

/pdf/synthesis-and-investigation-of-the-derivatives-of-2u7xlx8ge3.pdf

Synthesis and investigation of the derivatives of amidinohydrazonelated aromatic compounds as furin inhibitors

Furin, a human subtilisin-related proprotein convertase, is the most important pharmaceutical target because it plays a vital role in development of numerous disease processes. To identify a new class of small non-peptide inhibitors of furin we performed a study of several flavonoids and some natural products. Glycosylated flavonoids: rutin, naringin, baikalin and methylhesperidin were shown to inhibit furin at pH 7.2 reversibly and competitively with Ki- 80-200 microM. The Ki values were derived from Dixon and/or Eadie-Hofstee plots using fluorogenic substrate Boc-Arg-Val-Arg-Arg-AMC. Although studied flavonoids display only a temperate furin inhibition, they may serve as a great potential for the future development of more potent non-peptide inhibitors against furin.

[New non-peptide inhibitors of furin].

A series of novel non-peptidic furin inhibitors containing amidinohydrazone moieties has been synthesized under interaction of dialdehydes, the derivatives of ethylene diethylvanillin ethers, with aminoguanidine bicarbonate. Two aryl cycles were bridged by 1,2-ethylene-, 1,4-buthylene- or 1,4-dimethylenebenzene-group. The compounds have been found to inhibit furin. The antifurin activity was shown to grow with the increase of the length and/or hydrophobicity of the bridge. The most potent compound, containing in the bridge the lypophylic benzene cycle was found to inhibit the activity of furin with Ki = 0.51 microM.

/pdf/non-peptide-furin-inhibitors-based-on-amidinohydrazones-of-3glomlv202.pdf

[Non-peptide furin inhibitors based on amidinohydrazones of diarylaldehydes].

A series of 5-amino-1H-pyrazoles was synthesized and studied as inhibitors of furin. The most potent compound, 5-amino-4-acetylamino-3-(4-methylphenylamino)1H-pyrazole, was found to retard the activity of furin by mixed-type inhibition with K = 288 microM. These findings permit to plan new ways for chemical modifications of the 5-amino-1H-pyrazole structure and design more potent furin inhibitors of non-peptide nature.

Vadziuk Ob

Papers

[New non-peptide inhibitors of furin].

[Non-peptide furin inhibitors based on amidinohydrazones of diarylaldehydes].

[Study on derivatives of 5-amino-4-acylamino-1H-pyrazole as inhibitors of furin].