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Synthesis of Macrocyclic Polyamines and their Cu, Fe, Mn and Zn Complexes Targeting HIV (AIDS).
Date
2011Type
DissertationDepartment
Chemistry
Degree Level
Doctorate Degree
Abstract
Macrocyclic polyamines cyclotriazadisulfonamide (CADA) and bicyclam AMD3100 act as entry inhibitors against HIV by different mechanisms. The manganese complex of pyridine-fused macrocyclic polyamine (M40401) has been found to reduce HIV-1 induced apoptosis of astroglial cells. Based on these findings, seventeen new compounds were designed and synthesized, including five macrocyclic polyamines (<bold>SH07</bold>, <bold>SH09</bold>, <bold>SH25</bold>, <bold>SH26</bold>, <bold>SH28</bold>) and their copper (<bold>SH34</bold>, <bold>SH37</bold>), iron (<bold>SH35</bold>, <bold>SH38</bold>), manganese (<bold>SH06</bold>, <bold>SH08</bold>, <bold>SH15</bold>, <bold>SH16</bold>, <bold>SH21</bold>, <bold>SH23</bold>) and zinc (<bold>SH36</bold>, <bold>SH39</bold>) complexes. Moreover, synthesis of twelve previously reported compounds of biological interest is reported including macrocyclic polyamines and their copper, iron, manganese and zinc complexes (<bold>SH04</bold>, <bold>SH05</bold>, <bold>SH14</bold>, <bold>SH19</bold>, <bold>SH20</bold>, <bold>SH22</bold>, <bold>SH26</bold>, <bold>SH28</bold>, <bold>SH29</bold>, <bold>SH31</bold>, <bold>SH32</bold> and <bold>SH33</bold>). All the newly reported macrocyclic polyamines are characterized by <super>1</super>H and <super>13</super>C NMR spectroscopy, and ESI mass spectrometry. Additionally, microanalysis (<bold>SH07</bold> and <bold>SH09</bold>) and HRMS (<bold>SH26</bold>) data were obtained. All metal complexes are characterized by ESI MS and microanalysis. Testing of some of these compounds for inhibition of HIV replication in cell cultures uncovered five leads, SH06 (IC50 = 0.41 ± 0.06 μg/mL, CC50 = 20 μg/mL), SH15 (IC50 = 0.50 ± 0.16 μg/mL, CC50 = >100 μg/mL), SH16 (IC50 = 1.23 ± 0.50 μg/mL, CC50 = 51 μg/mL), SH34 (IC50 = 0.86 ± 0.35 μg/mL, CC50 = >100 μg/mL) and SH36 (IC50 = 0.49 ± 0.22 μg/mL, CC50 = >100 μg/mL). Testing of some more analogs SH28, SH37, SH38 and SH39 against HIV is in progress.
Permanent link
http://hdl.handle.net/11714/3949Additional Information
Committee Member | Frost, Brian J.; Jeffrey, Christopher S.; Pari, Gregory S.; Welch, William H. |
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Rights | In Copyright(All Rights Reserved) |
Rights Holder | Author(s) |
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