Lavendustin A

Eur J Med Chem. 2010 Sep;45(9):4288-92.

Synthesis and anticancer activity of chromone-based analogs of lavendustin A.[Pubmed: 20630626]

Lavendustin A and hormothamnione were reported to exhibit cytotoxic effects on tumor cell lines.
METHODS AND RESULTS:
In the present studies, a series of chromone-based Lavendustin Analogs were synthesized as a simplified hybrid of hormothamnione and Lavendustin A by the reductive-amination of formyl-chromone 5 with various amines followed by aminoalkylation.
CONCLUSIONS:
Most compounds synthesized showed significantly improved potencies compared to the standard compound 3 against most of cancer cell lines tested indicating that the removal of styryl group enhanced cancer cell growth inhibitory activities. Compound 4h and 4k showed the most potent inhibitory activities with GI(50) values in the range of 6.01-9.92 microg/ml on A-549 and HCT-15 cells.

J Biol Chem. 1991 Nov 5;266(31):21105-12.

Kinetic analysis of the inhibition of the epidermal growth factor receptor tyrosine kinase by Lavendustin-A and its analogue.[Pubmed: 1939153 ]

Lavendustin A was reported to be a potent tyrosine kinase inhibitor of the epidermal growth factor (EGF) receptor (Onoda, T., Iinuma, H., Sasaki, Y., Hamada, M., Isshibi, K., Naganawa, H., Takeuchi, T., Tatsuta, K., and Umezawa, K. (1989) J. Nat. Prod. 52, 1252-1257).
METHODS AND RESULTS:
Its inhibition kinetics was studied in detail using the baculovirus-expressed recombinant intracellular domain of the EGF receptor (EGFR-IC). Lavendustin A (RG 14355) is a slow and tight binding inhibitor of the receptor tyrosine kinase. The difference between the two values is due to the tight binding nature of the inhibitor to the enzyme in EI*. The kinetic analysis using a preincubation protocol to pre-equilibrate the enzyme with the inhibitor in the presence of one substrate showed that Lavendustin A is a hyperbolic mixed-type inhibitor with respect to both ATP and the peptide substrate, with a major effect on the binding affinities for both substrates.
CONCLUSIONS:
An analogue of Lavendustin A (RG 14467) showed similar inhibition kinetics to that of Lavendustin A.

J Med Chem. 2003 Apr 24;46(9):1670-82.

Synthesis, anticancer activity, and inhibition of tubulin polymerization by conformationally restricted analogues of lavendustin A.[Pubmed: 12699385]

METHODS AND RESULTS:
Compounds in the Lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain Lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK inhibitor piceatannol and the cis-stilbene structure of the tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the benzylaniline structure of a series of pharmacologically active Lavendustin A fragments was replaced by either their cis- or their trans-stilbene relatives, and effects on both inhibition of tubulin polymerization and cytotoxicity in cancer cell cultures were monitored.
CONCLUSIONS:
Two of the Lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of tubulin polymerization, which ranks them among the most potent of the known tubulin polymerization inhibitors.

Pflugers Arch. 1999 Feb;437(3):317-23.

Angiotensin II stimulation of Ca2+-channel current in vascular smooth muscle cells is inhibited by lavendustin-A and LY-294002.[Pubmed: 9914387]

Angiotensin II (AngII) is coupled to several important intracellular signaling pathways, and increases intracellular Ca2+.
METHODS AND RESULTS:
In vascular smooth muscle (VSM) cells, AngII is known to activate enzymes such as tyrosine protein kinase (Tyr-PK), phospholipase C (PLC), protein kinase C (PKC), and phophatidylinositol-3-kinase (PI-3-K). A non-receptor Tyr-PK, pp60(c-src), and PKC have been reported to stimulate the Ca2+ channels in VSM cells. However, less is known about AngII action on the voltage-gated Ca2+ channels. The Ca2+-channel currents of a cultured rat aortic smooth muscle cell line, A7r5, were recorded using whole-cell voltage clamp. Application of 50 nM AngII significantly increased the amplitude of Ba2+ currents through the voltage-gated Ca2+ channels (IBa) by 34. 5+/-9.1% (n=10) within 1 min. In the presence of lavendustin-A (5 microM), a selective inhibitor of Tyr-PK, AngII failed to stimulate IBa (n=5). AngII stimulation of IBa was also prevented by (5 microM) LY-294002, an inhibitor of PI-3-K (n=5). In contrast, H-7 (30 microM), an inhibitor of PKC, did not prevent the effect of AngII on IBa (n=6).
CONCLUSIONS:
These results suggest that AngII may stimulate the Ca2+ channels of VSM cells through Tyr-PK and PI-3-K under conditions that probably exclude participation of PK-C.

Jpn J Pharmacol. 1997 Jun;74(2):203-8.

Modulation of tyrosine kinase activity has multiple actions on insulin release from the pancreatic beta-cell: studies with lavendustin A.[Pubmed: 9243329]

METHODS AND RESULTS:
We investigated the role of tyrosine kinases in the regulation of insulin release from a hamster beta-cell line, HIT T15, using selective tyrosine kinase inhibitors. Genistein increased the insulin release induced by glucose, but herbimycin A, tyrphostins and the erbstatin analogue failed to change the release. Lavendustin A at 0.1 nM-1 microM caused a concave-shaped inhibition of the insulin release stimulated by 7 mM glucose. The inhibitory effect of Lavendustin A was overcome by higher concentrations of glucose. Lavendustin B, the negative control analogue, had no effect on the release. Lavendustin A at a nanomolar range progressively inhibited insulin release by high K+ (50 mM)-depolarization, whereas the inhibitor did not change the insulin release by Ca2+ ionophore (A23187). On the contrary, Lavendustin A at 10 nM significantly increased insulin release when glucose-induced insulin release was enhanced by either 5 microM forskolin or 162 nM 12-O-tetradecanoylphorbol 13-acetate. Lavendustin A failed to influence the Ca(2+)-induced insulin release from HIT cells permeabilized with streptolysin-O.
CONCLUSIONS:
These findings suggest that tyrosine kinases may play versatile roles in the control of insulin release from the pancreatic beta-cell.