| In recent years, with the development of the molecular mechanism research of viral replication in body, more and more cell protein required for the viral replication was confirmed, which became a new hotspot on the study of anti-virus infection by cell factor mechanism. A great deal of work on the study of anti-virus infection by cell factor mechanism has been carried out in our institution, and good results have been obtained such as the drug taking Hsp90 as the target. Based on the preliminary studies, a new broad-spectrum antibiotic for anti-virus geldanamycin was modified by the structure-activity relationship study for invention a new mechanism of the broad-spectrum antiviral drugs.In this article, the Hsp90 inhibitor-geldanamycin was taken as a lead compound, which aimed at decreased toxicity and increased stability. The modification was occurred on 17 and/or 19 site of geldanamycin. Eight synthesis lines were designed, in which seven synthesis lines were completed at last. In these lines, the line of 17 and 19 site disubstituted reaction was established at the first time. There were 118 synthesized compounds including 53 geldanamycin derivatives.46 geldanamycin derivatives were new structure compound.These derivatives were comprised of 23 alkylamine derivatives(Al-A22, F1),1 derivative of nucleoside(B1),4 derivatives of amino acid and dipeptide (C1,C2,C6,C7),1 sulfo derivative (C3),2 phosphate derivatives (C4,C5),2 amide derivatives (D1,D2),3 derivatives of hydroxide radical structure(E1-E3),4 derivatives of sugar structure(E4-E7), 11 derivatives of disubstituted reaction (G1-G11) and 1 hydroquinone derivatives(H2). All the structure of target compounds were corroborated by 1H NMR and MS.The study of antiviral activity in vitro was carried out. The results showed that most derivatives had antiviral activity. In the study of anti-HSV in vitro showed that the IC50 of HSV-lof Al, A2, A6, A13, A17, A18, A22 and G11 were 0.082,0.065,1.06,0.939,0.541, 0.866,0.20 and 1.28?g/ml. They had the same activity with geldanamycin (IC50= 0.975?g/ml) and better activity than positive drug-Aciclovir (IC50=1.49?g/ml), the IC50 of HSV-2 were 0.027,<0.009,1.04,0.968,0.703,2.34,0.05 and 0.74?g/ml. They had the same activity with geldanamycin (IC50=0.748?g/ml) and better activity than positive drug-Aciclovir (IC50=156?g/ml).The IC50 on anti-HIV of A6, A7, A13, A14, A16 and A20 were 0.0284,0.013,0.0976,0.0736,0.0783 and 0.04?g/ml. They had the same activity with lead compound (IC50<0.0305?g/ml). The derivatives A3,A13, A16, A17, El, G3 and G11 had a better activity of anti-HBV in vitro (IC50=0.24,0.01,0.009,0.081,0.119,0.105 and 0.17?g/ml) than Lamivudine (IC50=0.84?g/ml). Although the IC5o of A5, A6, A16 and A21 (IC50=0.08,0.03,0.05,0.11) were lower than lead compound (IC50=0.0048?g/ml) excepted C4(0.002?g/ml) was higher than lead compound, the selected indexes of anti-HCV about these derivatives were higher than lead compound. In addition, the derivative of A5 had a good activity of anti-VSV (IC50=0.479?g/ml) and Cox B3, B6 (IC50=3.55?g/ml; 0.099?g/ml). However, the influenza virus A and B were not sensitive to derivatives.The study of activity for anti-HSV in vivo showed that the anti-HSV-1 and HSV-2 activity from the serum of mice administration A11 by ig higher than lead compound and Aciclovir. The anti-HSV-2 activity from the serum of mice administration A4 by ig was higher than lead compound and Aciclovir.The study of activity for anti-DHBV in vivo showed that, administration a 5, A16, A17 and E2 by ig, the DHBV DNA in the group of A5,A16, A17, E2 were decreased statistically significant difference(P<0.01). Compared with all treatment groups and control group, the DHBV DNA was decreased obviously. The antivirual activity in vivo of A5 and A16 were higher than Lamivudine.The results of toxicity in vitro showed that the derivatives of A13, A17 and A22 had the same toxicity as lead compound, and obviously higher than others. The toxicity of other derivatives were lower than lead compound, the TC50 were about 10-100 times of lead compound. In a acute toxicity test, the LD50 of Geldanamycin was 15.45mg/kg, the derivatives of 17-substituted were about 10-20 times and the derivatives of 17, 19-disubstituted were about 40 times of lead compound.The water-solubility of most of derivatives was improved (more than 10 times). The results of oil-water distribution coefficient (logP) showed that most of derivatives was suitable for intestinal absorption. A good bioavailability could be expected. The light stability of A5 and A16 have a huge raise to geldanamycin, their half-life was 30-50 times to lead compound.The single dose oral drug delivery study of A5 and A16 were studied. The results showed that 2 derivatives have good pharmacokinetic properties. They were suitable for oral administration.In a word, by the structural optimization, some new broad-spectrum anti-virus candidate derivatives were synthesised, which have a higher or similar antiviral activitythan Geldanamycin, more lower toxicity, and significant improvement on Physical, Chemical and pharmacokinetic properties. Derivatives of A5 and A16 have a lower toxicity and better broad-spectrum activity of antivirus than the lead compound and other derivatives, which showed a bright future in anti-virus... |
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