Advances in flavonoid research since 1992.

Pharmacological activities of natural triterpenoids and their therapeutic implications

Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

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An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

Pharmacological properties of the ubiquitous natural product betulin.

A growing solid tumor relies on a developing vasculature to meet its needs in terms of oxygen, nutrients, depuration, etc. This implies that if the vascular bed that has developed within the tumoral mass can be made to collapse, tumoral growth can be significantly hampered. Indeed, the first proof of principle that this could be achieved was provided more than 10 years ago when a ricin-conjugated antibody directed against an endothelial protein was able to eradicate the tumoral mass in mice.1-4 Therapeutically, two pharmacological strategies can be foreseen that stand on this observation: (1) the development of the growing tumoral vasculature can be arrested by drugs; (2) the established vasculature perfusing the tumoral mass can be destroyed by drugs. Among the crucial questions in the field is how to specifically target the endothelial cells participating in the tumoral neovasculature without causing damage to vasculature elsewhere. A wide body of data has emerged over this issue. 3 It has now been shown that the developing vasculature and the tumoral vasculature express unique proteins and that this uniqueness can be used for selective pharmacological targeting. Indeed, if we consider a plasma membrane protein expressed solely on the undesired vasculature, we could envisage the use of specific antibodies conjugated with toxins, vaccines, etc.3 Yet it is also possible that the neovasculature is more sensitive over normal tissues to more traditional small-molecule drugs. Indeed, this strategy has also been exploited, and a number of compounds have entered or are entering clinical trials (these drugs are cumulatively referred to as low molecular weight vasculature-disrupting agents). 4 For example, the growth of the neovasculature is dependent on activation of the vascular endothelial growth factor receptor, and therefore, a number of receptor antagonists have been devised and are currently tested or employed. 5 Disruption of tubulin polymerization also disrupts the formation of tumoral vasculature, and it is therefore no surprise that a number of agents have been brought forward into the drug pipeline that share this mechanism of action. The present review will concentrate primarily on the medicinal chemistry of one of these drugs, combretastatin A4 (CA-4 a

Medicinal chemistry of combretastatin A4: present and future directions.

Two phenanthrenes were isolated from the aerial part of Dendrobium nobile Lindl. and their structures were identified to be 4,7-dihydroxy-2-methoxy-9,10-dihydrophenanthrene (1) and denbinobin (2), among which the former has been first isolated from this plant. These two compounds were found to be cytotoxic against A549 (human lung carcinoma), SK-OV-3 (human ovary adenocarcinoma), and HL-60 (human promyelocytic leukemia) cell lines. Compound 1 also showed antitumor activity on the life span of ICR mice intraperitoneally implanted with 1 x 10(6) cells of sarcoma 180.

In Vitro and In Vivo Antitumoral Phenanthrenes from the Aerial Parts of Dendrobium nobile

In the search for antiangiogenic agents from medicinal plants used in Vietnam, a methanol extract of the stem barks of Bombax ceiba was found to exhibit a significant antiangiogenic activity on in vitro tube formation of human umbilical venous endothelial cells (HUVEC). Bioactivity-guided fractionation and isolation carried out on this extract afforded lupeol as an active principle. At 50 and 30 microg/mL lupeol showed a marked inhibitory activity on HUVEC tube formation while it did not affect the growth of tumor cell lines such as SK-MEL-2, A549, and B16-F10 melanoma.

Antiangiogenic activity of lupeol from Bombax ceiba

Seventeen saponins isolated from the root of Pulsatilla koreana were examined for their in vitro cytotoxic activity against the human solid cancer cell lines, A-549, SK-OV-3, SK-MEL-2, and HCT15, using the SRB assay method, and their in vivo antitumor activity using BDF1 mice bearing Lewis lung carcinoma (LLC). The saponins 5-17, with a free acidic functional group at C-28 of aglycon, exhibited moderate to considerable cytotoxic activity, however, the saponins 1-4, esterified with a trisaccharide at C-28 of aglycon, did not exhibit cytotoxic activity (ED50; >300 microM). Among them, oleanolic acid 3-O-alpha-L-rhamnopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->4)]-alpha-L-arabinopyranoside (10) exhibited the most potent cytotoxic activity (ED50; 2.56, 2.31, 1.57, 8.36 microM, respectively). In vivo test, hederagenin 3-O-alpha-L-rhamnopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->4)]-alpha-L-arabinopyranoside (6, Inhibition Ratio, IR; 66.9%) exhibited more potent antitumor activity than taxol (IR; 35.8%) and doxorubicin (IR; 62.1%). Also, hedragenin 3-O-beta-D-glucopyranosyl-(1-->4)-O-beta-D-glucopyranosyl-(1-->3)-O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside (17, IR; 50.3%) exhibited potent antitumor activity. These two saponins were identically comprised of a hederagenin aglycon moiety and a sugar sequence O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside at C-3 of the hederagenin, suggesting that the two elements are essential factors for the antitumor activity.

https://www.jstage.jst.go.jp/article/cpb/53/11/53_11_1451/_pdf

Antitumor activity of Pulsatilla koreana saponins and their structure-activity relationship.

Synthesis and cytotoxic activity of a-ring modified betulinic acid derivatives

The petroleum ether fraction of Pulsatilla koreana (Ranunculaceae) was found to have an inhibitory effect on the tube-like formation of human umbilical venous endothelial (HUVE) cells and strong cytotoxic activity against five tumor cell lines. The active component isolated from the fraction was deoxypodophyllotoxin (DPT). The cytotoxic activity against the tumor cells comprising the A549, SK-OV-3, SK-MEL-2, HCT15, and B16F10 cell lines, expressed as ED50, ranged from 6 to 18 ng/ml. 3 ng/ml of DPT, a concentration considerably below the cytotoxic concentration, completely inhibited the tube-like formation of HUVE cells. Furthermore, DPT exhibited an inhibition ratio of 60 % on BDF1 mice bearing Lewis lung carcinoma cells. The inhibitory effect on the tube-like formation was suggested to play an important role in antitumor activity.

Byung Zun Ahn

Papers

In Vitro and In Vivo Antitumoral Phenanthrenes from the Aerial Parts of Dendrobium nobile

Antiangiogenic activity of lupeol from Bombax ceiba

Antitumor activity of Pulsatilla koreana saponins and their structure-activity relationship.

Synthesis and cytotoxic activity of a-ring modified betulinic acid derivatives

Deoxypodophyllotoxin; The cytotoxic and antiangiogenic component from Pulsatilla koreana