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A series of twenty-three linear and branched chain mono acetylene lipids were isolated from the Caribbean Sea sponge <i>Cribrochalina vasculum</i>. Seventeen of the compounds, <b>1–17</b>, are new, while six, <b>18–23</b>, were previously characterized from the same sponge. Some of the new acetylene-3-hydroxy alkanes <b>1</b>, <b>6</b>, <b>7</b>, <b>8</b>, <b>10</b> were tested for selective cytotoxicity in non-small cell lung carcinoma (NSCLC) cells over WI-38 normal diploid lung fibroblasts. Compound <b>7</b>, presented clear tumor selective activity while, <b>1</b> and <b>8</b>, showed selectivity at lower doses and <b>6</b> and <b>10</b>, were not active towards NSCLC cells at all. The earlier reported selective cytotoxicity of some acetylene-3-hydroxy alkanes (<b><i>scal</i>-18</b> and <b>23</b>), in NSCLC cells and/or other tumor cell types were also confirmed for <b>19</b>, <b>20</b> and <b>22</b>. To further study the structure activity relationships (SAR) of this group of compounds, we synthesized several derivatives of acetylene-3-hydroxy alkanes, <i>rac</i>-<b>18</b>, <i>scal-S</i>-<b>18</b>, <i>R</i>-<b>18</b>, <i>rac</i>-<b>27</b>, <i>rac</i>-<b>32</b>, <i>R</i>-<b>32</b>, <i>S</i>-<b>32</b>, <i>rac</i>-<b>33</b>, <i>rac</i>-<b>41</b>, <i>rac</i>-<b>42</b>, <i>rac</i>-<b>43</b>, <i>rac</i>-<b>45</b>, <i>rac</i>-<b>48</b> and <i>rac</i>-<b>49</b>, along with other 3-substituted derivatives, <i>rac</i>-<b>35</b>, <i>rac</i>-<b>36</b>, <i>rac</i>-<b>37</b>, <i>rac</i>-<b>38</b>, <i>rac</i>-<b>39</b> and <i>rac</i>-<b>40</b>, and assessed their cytotoxic activity against NSCLC cells and diploid fibroblasts. SAR studies revealed that the alcohol moiety at position 3 and its absolute <i>R</i> configuration both were essential for the tumor cell line selective activity while for its cytotoxic magnitude the alkyl chain length and branching were of less significance.