84
D.C. Hill et al.
a difference in cell growth between transformed and normal cells as its detection
system [40]. Angelmicin B had no effect on ras transformed ceils but specifically
inhibited abl and src transformed cells via selective inhibition of tyrosine
kinases.
2.3 Cardiovascular Disease
Platelet aggregation and new blood vessel formation assays have been used in
the discovery and characterisation of novel microbial metabolites potentially
active in cardiovascular disease.
2.3.1 Inhibition of Platelet Aggregation
Platelet aggregation inhibitors may be useful in the treatment of vascular
disorders. FK409, a novel inhibitor of platelet aggregation, was assayed in
a turbidimetric assay for observing thrombin-induced rabbit platelet aggregation [41]. In addition, FK409 levels in the spent medium were quantified by
measuring relaxation activity on noradrenaline-induced contraction of rat
aorta.
FK409 (Fig. 2) is a semi-artificial bio-product of Streptomyces griseosporus
[42]. It is a hexenamide derivative bearing nitro- and oxime functions generated
from a precursor by the presence of sodium nitrite in the medium under acidic
conditions.
FK409 exhibited a marked relaxation activity on rat aorta and showed
a hypotensive effect equal to that of nitroglycerin, a drug used in the treatment
of angina pectoris, when tested in vivo.
Further platelet aggregation inhibitors which have been found using similar
assay systems include the naphthalenecarboxylic acid derivatives PI-200
and PI-201 from a Streptomycyes sp. [43], which are weak inhibitors of
ADP-induced aggregation of rabbit platelets, and Sch 38519, a novel isochromanequinone produced by a Thermomonospora sp. [44, 45], which is
reported to be a weak inhibitor of thrombin-induced aggregation of human
platelets.
Another related approach resulted in the identification of a basidiomycete
metabolite, which may inhibit platelet aggregation by acting at the thromboxane A2 receptor. Thromboxane A2 (TxAz) is the main product of
arachidonic acid metabolism in platelets, and a very potent inducer of platelet
aggregation and vasoconstriction. Collagen-induced bovine platelet aggregation assays were performed in microtitre plates leading to the discovery
of 2-methoxy-5-methyl-l,4-benzoquinone (MMB) produced by Lentinus
adhaerans [46]. Further biological characterisation of MMB suggested that it is
a competitive TxAa receptor antagonist.
D.C. Hill et al.
a difference in cell growth between transformed and normal cells as its detection
system [40]. Angelmicin B had no effect on ras transformed ceils but specifically
inhibited abl and src transformed cells via selective inhibition of tyrosine
kinases.
2.3 Cardiovascular Disease
Platelet aggregation and new blood vessel formation assays have been used in
the discovery and characterisation of novel microbial metabolites potentially
active in cardiovascular disease.
2.3.1 Inhibition of Platelet Aggregation
Platelet aggregation inhibitors may be useful in the treatment of vascular
disorders. FK409, a novel inhibitor of platelet aggregation, was assayed in
a turbidimetric assay for observing thrombin-induced rabbit platelet aggregation [41]. In addition, FK409 levels in the spent medium were quantified by
measuring relaxation activity on noradrenaline-induced contraction of rat
aorta.
FK409 (Fig. 2) is a semi-artificial bio-product of Streptomyces griseosporus
[42]. It is a hexenamide derivative bearing nitro- and oxime functions generated
from a precursor by the presence of sodium nitrite in the medium under acidic
conditions.
FK409 exhibited a marked relaxation activity on rat aorta and showed
a hypotensive effect equal to that of nitroglycerin, a drug used in the treatment
of angina pectoris, when tested in vivo.
Further platelet aggregation inhibitors which have been found using similar
assay systems include the naphthalenecarboxylic acid derivatives PI-200
and PI-201 from a Streptomycyes sp. [43], which are weak inhibitors of
ADP-induced aggregation of rabbit platelets, and Sch 38519, a novel isochromanequinone produced by a Thermomonospora sp. [44, 45], which is
reported to be a weak inhibitor of thrombin-induced aggregation of human
platelets.
Another related approach resulted in the identification of a basidiomycete
metabolite, which may inhibit platelet aggregation by acting at the thromboxane A2 receptor. Thromboxane A2 (TxAz) is the main product of
arachidonic acid metabolism in platelets, and a very potent inducer of platelet
aggregation and vasoconstriction. Collagen-induced bovine platelet aggregation assays were performed in microtitre plates leading to the discovery
of 2-methoxy-5-methyl-l,4-benzoquinone (MMB) produced by Lentinus
adhaerans [46]. Further biological characterisation of MMB suggested that it is
a competitive TxAa receptor antagonist.