Tubulin-polymerization inhibitors derived from thalidomide

2-(2,6-Diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent tubulin-polymerization-inhibiting activity, comparable to that of the known tubulin-polymerization inhibitors, rhizoxin and colchicine. A major metabolite of thalidomide, 5-hydroxythalidomide, which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, also showed moderate inhibitory activity.     

Angiogenesis inhibitors derived from thalidomide

5-Hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33: 10), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent anti-angiogenic activity in a human umbilical vein endothelial cell (HUVEC) assay. Thalidomide (1) and its metabolite, 5-hydroxythalidomide (5-HT: 2), which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, as well as IMiDs (immunomodulatory derivatives of thalidomide: 3 and 5), also showed weak or moderate activity in the same assay.     

Cell differentiation inducers derived from thalidomide

5-Hydroxy- and 4-amino-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33 and 4APP-33, respectively) have been shown to possess cell differentiation-inducing activity toward human leukemia cell line HL-60.     

Phenylhomophthalimide-type NOS inhibitors derived from thalidomide

Thalidomide shows moderate inhibitory activity toward neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), but not toward endothelial NOS (eNOS). Structural development studies of thalidomide yielded novel phenylhomophthalimide-type NOS inhibitors with enhanced activity and different subtype selectivity.     

Development of tryptase inhibitors derived from thalidomide

A novel series of tryptase inhibitors with a N-phenylphthalimide skeleton structurally derived from thalidomide (1) has been developed. Structure–activity relationship studies led to a potent and selective tryptase inhibitor, 2-(4-cyanophenyl)isoindole-1,3-dione-5-yl 3-(2-aminopyridin-5-yl)propanoate (7), with the IC₅₀ value of 78 nM.     

Inhibitors of the LPS-induced NF-kappaB activation from Artemisia sylvatica

Three guaianolide sesquiterpene lactones, 3alpha,4alpha-epoxyrupicolins C-E, together with six known sesquiterpenes, artemisolide, 3-methoxytanapartholide, deacetyllaurenobiolide, moxartenolide as well as arteminolides B and D were isolated by bioassay-guided fractionation from the methanol extract of the aerial parts of Artemisia sylvatica using the NF-kappaB mediated reporter gene assay. All isolated compounds displayed inhibitory activity on the LPS-induced NF-kappaB activation, NO production, and TNF-alpha production with IC50 values of 0.49-7.17, 1.46-6.16, and 3.19-27.76 microM, respectively, in RAW264.7 cells. It was also established that arteminolide B suppressed the expression of NF-kappaB target genes such as iNOS and COX-2. This is the first report of NF-kappaB inhibitory activities of these compounds and supports the pharmacological use of Artemisia sylvatica, which has been employed as an herbal medicine for the treatment of inflammation.     

Synthesis of NF-kappaB activation inhibitors derived from epoxyquinomicin C

In order to develop new inhibitors of NF-kappaB activation, we designed and synthesized dehydroxymethyl derivatives of epoxyquinomicin C, namely, DHM2EQ and its regioisomer DHM3EQ. These derivatives were synthesized from 2,5-dimethoxyaniline in 5 steps. Since DHM2EQ was more active and less toxic than DHM3EQ, its stereochemical configuration was determined by X-ray crystallographic analysis. Each enantiomer of the protected DHM2EQ was separated by a chiral column and deprotected. DHM2EQ inhibited TNF-alpha-induced activation of NF-kappaB in human T cell leukemia cells, and also inhibited collagen-induced arthritis in a rheumatoid model in mice.     

Tubulin polymerization inhibitors with a fluorinated phthalimide skeleton derived from thalidomide

4,7-Difluoro-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione [4,7FPP-33 (14)] has a potent tubulin-polymerization-inhibiting activity comparable with those of the known tubulin-polymerization inhibitors rhizoxin and colchicine. The structure-activity relationship for fluorine substitution was elucidated.     

Design and synthesis of subtype-selective cyclooxygenase (COX) inhibitors derived from thalidomide

A series of substituted indoline and indole derivatives with cyclooxygenase (COX)-inhibitory activity was prepared during our structural development studies based on thalidomide as a multi-template lead compound. Structure-activity relationship studies indicated that the nature of the substituent introduced at the benzene ring of the indoline (indole) backbone, and the length and type of the linking group between the nitrogen atom of indoline (indole) and the N-substituent are important for the activity. This study has led to the identification of COX-1-selective inhibitors, and these should be useful not only as pharmacological tools to investigate the physiology and pathophysiology of COX, but also as sophisticated leads for the development of novel drugs to treat COX-associated diseases, such as inflammatory diseases, and cancer.     

Neuraminidase Inhibitors from marine‐derived actinomycete Streptomyces seoulensis

Aims

This work was performed to characterize new secondary metabolites with neuraminidase (NA) inhibitory activity from marine actinomycete strains.

Methods and Results

An actinomycete strain IFB‐A01, capable of producing new NA inhibitors, was isolated from the gut of shrimp Penasus orientalis and identified as Streptomyces seoulensis according to its 16S rRNA sequence (over 99% homology with that of the standard strain). Repeated chromatography of the methanol extract of the solid‐substrate culture of S. seoulensis IFB‐A01 led to the isolation of streptoseolactone ( 1 ), and limazepines G ( 2 ) and H ( 3 ). The structures of 1 – 3 were determined by a combination of IR, ESI‐MS, 1D (¹H and ¹³C NMR, and DEPT) and 2D NMR experiments (HMQC, HMBC, ¹H‐¹H COSY and NOESY). Compounds 1 – 3 showed significant inhibition on NA in a dose‐dependent manner with IC₅₀ values of 3·92, 7·50 and 7·37 μmol l^?1, respectively.

Conclusions

This is the first report of two new ( 1 and 2 ) and known ( 3 , recovered as a natural product for the first time in the work) NA inhibitors from the marine‐derived actinomycete S. seoulensis IFB‐A01.

Significance and Impact of the Study

The three natural NA inhibitors maybe of value for the development of drug(s) necessitated for the treatment of viral infections.     

A Link Between Histone Deacetylase Inhibitors and NF-kappaB Signaling

Commentary to:

An Intact NF-κB Pathway is Required for Histone Deacetylase Inhibitor-Induced G₁ Arrest and Maturation in Human Myeloid Leukemia (U937)

Yun Dai, Mohamed Rahmani, Steven Grant     

Osteoprotegerin reduces the serum level of receptor activator of NF-kappaB ligand derived from osteoblasts

Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-kappaB ligand (RANKL). We previously reported that OPG deficiency elevated the circulating level of RANKL in mice. Using OPG(-/-) mice, we investigated whether OPG is involved in the shedding of RANKL by cells expressing RANKL. Osteoblasts and activated T cells in culture released a large amount of RANKL in the absence of OPG. OPG or a soluble form of receptor activator of NF-kappaB (the receptor of RANKL) suppressed the release of RANKL from those cells. OPG- and T cell-double-deficient mice showed an elevated serum RANKL level equivalent to that of OPG(-/-) mice, indicating that circulating RANKL is mainly derived from bone. The serum level of RANKL in OPG(-/-) mice was increased by ovariectomy or administration of 1alpha,25-dihydroxyvitamin D(3). Expression of RANKL mRNA in bone, but not thymus or spleen, was increased in wild-type and OPG(-/-) mice by 1alpha,25-dihydroxyvitamin D(3). These results suggest that OPG suppresses the shedding of RANKL from osteoblasts and that the serum RANKL in OPG(-/-) mice exactly reflects the state of bone resorption.     

Inhibitors of NF-kappaB signaling: design and synthesis of a biotinylated isopanepoxydone affinity reagent

A number of inhibitors of NF-kappaB signaling arising from our recent syntheses of isopanepoxydone and panepoxydone have been identified. Structure-activity data have been correlated to allow the design and synthesis of an affinity reagent for the isolation and identification of any relevant cellular target.     

Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886

A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.     

Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling

A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively.