Triazole tethered C 5 -curcuminoid-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies

1区 · 医学

Article

作者: Nepali, Kunal ; Kumar, Mandeep ; Bedi, Preet Mohinder S ; Sharma, Sahil ; Gupta, Manish K ; Saxena, Ajit K ; Singh, Harbinder

Keeping in view the confines allied with presently accessible antitumor agents and success of C5-curcuminoid based bifunctional hybrids as novel antitubulin agnets, molecular hybrids of C5-curcuminoid and coumarin tethered by triazole ring have been synthesized and investigated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and PC-3 human tumor cell lines. The results revealed that the compounds A-2 to A-9, B-2, B-3, B-7 showed significant cytotoxic potential against THP-1, COLO-205 and HCT-116 cell lines, while the PC-3 cell line among these was found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and the length of carbon-bridge (n) connecting triazole ring with coumarin moiety considerably influence the activity. Methoxy substituted phenyl ring as Ring X and two carbon-bridges were found to be the ideal structural features. The most potent compounds (A-2, A-3 and A-7) were further tested for tubulin polymerization inhibition. Compound A-2 was found to significantly inhibit the tubulin polymerization (IC50 = 0.82 μM in THP-1 tumor cells). The significant cytotoxicity and tubulin polymerization inhibition by A-2 was further rationalized by docking studies where it was docked at the curcumin binding site of tubulin.

1995-06-01·The Journal of allergy and clinical immunology1区 · 医学

Natural and recombinant enzymatically active or inactive bee venom phospholipase A 2 has the same potency to release histamine from basophils in patients with Hymenoptera allergy

1区 · 医学

Article

作者: Forster, Elisabeth ; Urbanek, Radvan ; Suter, Mark ; Gmachl, Michael ; Dudler, Thomas ; Aberer, Werner

BACKGROUND:

A complementary DNA encoding the major bee venom allergen phospholipase A2 (PLA) has been characterized recently. Recombinant PLA was produced in Escherichia coli and purified to apparent homogeneity. Natural PLA was compared with recombinant PLA in its ability to release histamine from blood basophils.

METHODS:

A synthetic gene encoding the mature form of PLA was expressed in E. coli, and the polypeptide was purified to homogeneity by affinity chromatography and refolded, yielding fully enzymatically active PLA. In addition, we have produced a genetically engineered enzymatically inactive variant by substitution of a single amino acid residue in the catalytic center. A standard histamine release assay was used to compare the potency of natural PLA with correctly folded enzymatically active and inactive recombinant PLA to release histamine from blood basophils of nine patients with bee venom allergy.

RESULTS:

Recombinant enzymatically active PLA and purified natural protein were equally effective in releasing histamine from sensitized basophils. By comparing the histamine-releasing capacity of enzymatically active and inactive recombinant allergen, we further demonstrate that catalytic activity is not a requirement for allergenicity in the effector phase. Denaturation of natural PLA or incorrect folding of recombinant protein resulted in a total loss of allergenic potency.

CONCLUSION:

We demonstrate the feasibility of producing native-like recombinant allergens with or without enzymatic activity. We also provide evidence for the requirement of correct three-dimensional structure of PLA to induce histamine release from basophils and thus evidence for its recognition by IgE.

1988-02-01·Biulleten' eksperimental'noi biologii i meditsiny

[Paradoxical correlations of the effectiveness of the intranasal and intraperitoneal administration of dermorphins in rats].

Article

作者: Kamenskiĭ, A A ; Sarycheva, N Iu ; Baturina, E Iu ; Iarova, E P ; Deĭgin, V I

The analgetic activity of dermorphin and its analogue A-2 was assessed by the tail-flick test. Following intraperitoneal administration at doses 5 mg/kg and above the peptides showed significant effects. After intranasal application of the peptides a significant effect was observed in the range of low doses 0.001-0.1 mg/kg. After intranasal application of high dermorphin doses (1 or 5 mg/kg) the analgetic activity decreased. The effect of analogue A-2 lasted longer after intranasal, than after intraperitoneal administration. It is assumed that the neurophysiological mechanisms of the analgetic activity of dermorphins depend on the route of their administration.

100 项与 A-02( Hangzhou Converd) 相关的药物交易

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