Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris

Abstract

Background and Purpose Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic®, a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)‐DBZ and (R)‐DBZ isomers in vitro and in vivo. Experimental Approach A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. Key Results DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12‐day co‐culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP‐9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. Conclusions and Implications These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.

A novel compound DBZ ameliorates neuroinflammation in LPS-stimulated microglia and ischemic stroke rats: Role of Akt(Ser473)/GSK3β(Ser9)-mediated Nrf2 activation

“…Dantonic®, a composite Danshen formulation containing standardized extracts of Salviae miltiorrhiza and Panax notoginseng plus borneol, has been broadly used in China for the treatment of myocardial and cerebral ischemic diseases for many decades, and has already completed Phase III clinical trials in the USA (NCT01659580). Inspired by the principle of TCM combinatorial formulations and our previous findings [ [38] , [39] , [40] , [41] , [42] , [43] ], we designed and synthesized tanshinol borneol ester (DBZ, 1,7,7-trimethylbicyclo [2.2.1]heptan-2-yl-3-(3,4-dihydroxyphenyl)-2-hydroxy-propanoate) by chemical combination of tanshinol and borneol (core effective components of Dantonic®) as well as a library of related compounds based on our drug design strategy [ 44 ]. Based on in silico , in vitro and in vivo screenings, DBZ is found to be a safe and a highly pleiotropic molecule endowed with a wide range of beneficial activities, including pro-angiogenic, anti-inflammatory, anti-atherosclerotic and cardiovascular protective effects [ [44] , [45] , [46] , [47] ].…”

Clavukoellians G–K, New Nardosinane and Aristolane Sesquiterpenoids with Angiogenesis Promoting Activity from the Marine Soft Coral Lemnalia sp.

“…Since the angiogenesis-related activities shown in clavukoellians [7], we are committed to find more nardosinane analogues with angiogenesis activity. The anti-and pro-angiogenesis activities of compounds 1-5 were evaluated in a transgenic fluorescent zebrafish (Tg(vegfr2:GFP)) model [12][13][14][15]. Quantitative analysis revealed that compound 5 displayed pro-angiogenesis activity in a PTK787-induced vascular injury zebrafish model at 2.5 μM (Figure 4).…”

“…Clavukoellian G (1) and clavukoellian H (2) are the fifth and sixth members of the nitrogen-containing nardosinane sesquiterpenes family so far. Clavukoellian I (3) represents a 6/6/6 tricyclic skeleton with a ∆ 11,12 double bond which is rare in this structure family. Clavukoellian J (4) is a C6-C7 cleavage seco-nardosinane-type sesquiterpene related to clavukoellian E. Clavukoellian K (5) is a new aristolane-type sesquiterpenoid.…”

“…The conditions of the maintenance were complied with guidelines of the Organization for Economic Co-operation and Development (OECD). The zebrafish were maintained under a 14/10 h light/dark cycle at the temperature (28 ± 0.5 • C) in a closed flow-through system with charcoal-filtered tap water to ensure normal spawning [12][13][14][15].…”

“…Each zebrafish larva was photographed by a fluorescence microscope (AXIO, Zom.V16), and the length of intersomitic vessels (ISV) was calculated through Image-Pro Plus software. One-way analysis of variance was calculated by GraphPad Prism 7.00 software [12][13][14][15].…”