Synthesis of Macrocyclic Polyamines and their Cu, Fe, Mn and Zn Complexes Targeting HIV (AIDS).

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 &plusmn; 0.06 &mu;g/mL, CC50 = 20 &mu;g/mL), SH15 (IC50 = 0.50 &plusmn; 0.16 &mu;g/mL, CC50 = >100 &mu;g/mL), SH16 (IC50 = 1.23 &plusmn; 0.50 &mu;g/mL, CC50 = 51 &mu;g/mL), SH34 (IC50 = 0.86 &plusmn; 0.35 &mu;g/mL, CC50 = >100 &mu;g/mL) and SH36 (IC50 = 0.49 &plusmn; 0.22 &mu;g/mL, CC50 = >100 &mu;g/mL). Testing of some more analogs SH28, SH37, SH38 and SH39 against HIV is in progress.