Discovery, semisynthesis, biological activities, and metabolism of ocotillol-type saponins

Triterpenes are structurally complex plant natural products with numerous medicinal applications. They are synthesized through an origami-like process that involves cyclization of the linear 30 carbon precursor 2,3-oxidosqualene into different triterpene scaffolds. Here, through a forward genetic screen in planta, we identify a conserved amino acid residue that determines product specificity in triterpene synthases from diverse plant species. Mutation of this residue results in a major change in triterpene cyclization, with production of tetracyclic rather than pentacyclic products. The mutated enzymes also use the more highly oxygenated substrate dioxidosqualene in preference to 2,3-oxidosqualene when expressed in yeast. Our discoveries provide new insights into triterpene cyclization, revealing hidden functional diversity within triterpene synthases. They further open up opportunities to engineer novel oxygenated triterpene scaffolds by manipulating the precursor supply.

https://www.pnas.org/content/pnas/113/30/E4407.full.pdf

A conserved amino acid residue critical for product and substrate specificity in plant triterpene synthases

Staphylococcus aureus infections are considered as seriously problematic for human health and necessitate the development of new medicines and innovative antimicrobial strategies. Plant secondary metabolites have already demonstrated their potential as antibacterials when used alone but also in combination with other antimicrobial agents to potentiate their activity. Triterpenoids are widely distributed in the plant kingdom and known to have many beneficial effects, including anti-inflammatory, immunomodulatory, anti-proliferative, antimycotic, or antimicrobial activity. The aim of this paper is to review the activity of pentacyclic triterpenoids belonging to the ursane, oleanane, or lupane groups against Staphylococcus aureus. We summarize their activity as anti-staphylococcal compounds but also as resistance modifying agents when combined with common antibiotics.

Natural and hemi-synthetic pentacyclic triterpenes as antimicrobials and resistance modifying agents against Staphylococcus aureus: a review

Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [3H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function.

/pdf/semi-synthetic-ocotillol-analogues-as-selective-abcb1-23ouko3a4l.pdf

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

Design, synthesis, nitric oxide release and antibacterial evaluation of novel nitrated ocotillol-type derivatives.

Synthesis and biological evaluation of novel ocotillol-type triterpenoid derivatives as antibacterial agents.

The invention relates to the fields of organic synthesis and pharmacochemistry, particularly (20S,24S)-ocotillol ginsenoside derivatives, of which the structure is disclosed as general formula (I). The invention also discloses a preparation method of the (20S,24S)-ocotillol ginsenoside derivatives, a pharmaceutical composition containing the (20S,24S)-ocotillol ginsenoside derivatives, and application of the (20S,24S)-ocotillol ginsenoside derivatives in bacterial infection disease inhibition. General formula (I).

(20S,24S)-ocotillol ginsenoside derivatives with antibacterial activity, and preparation method and application thereof

Targeting the colchicine binding site on tubulin is a promising strategy to develop cancer therapeutics. Herein, we describe our systematic structure-activity relationship studies of benzamide derivatives that lead to an identification of a potent and orally active tubulin inhibitor 48, which occupied all three zones of the colchicine binding site in the X-ray co-crystal structure, inhibited tubulin polymerization, promoted mitotic blockade and apoptosis, and exhibited significant antiproliferative activities against various cancer cell lines. Compound 48 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacies, and acceptable safety profiles. Furthermore, 48 overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, 48 has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.

Optimization of Benzamide Derivatives as Potent and Orally Active Tubulin Inhibitors Targeting the Colchicine Binding Site.

Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.

Hua Tian

Papers

Synthesis and biological evaluation of novel ocotillol-type triterpenoid derivatives as antibacterial agents.

(20S,24S)-ocotillol ginsenoside derivatives with antibacterial activity, and preparation method and application thereof

Optimization of Benzamide Derivatives as Potent and Orally Active Tubulin Inhibitors Targeting the Colchicine Binding Site.

Design and Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for the Treatment of B-Cell Malignancies.

Bioevaluation of a dual PI3K/HDAC inhibitor for the treatment of diffuse large B-cell lymphoma.