The first synthesis of the ent-labdane diterpenoid (−)-agathic acid (1) with antibacterial activity is described. A chiral pool approach was employed with a linear sequence of 14 steps starting from readily available and inexpensive andrographolide. The regioselective deoxygenation in terms of Barton-McCombie free radical reaction completed a key step in the synthesis. (−)-Copalic acid (2), an analogue of (−)-agathic acid, has been conveniently synthesized from the key intermediate 7 in five steps.

The synthesis of a series of andrographolide-19-oic acid derivatives was described and their in vitro anti-tumor activity against two human cell lines was evaluated. Most compounds were found to exhibit significant cytotoxicity, better than andrographolide, and compounds 9d and 9b were identified as the most potent with IC50 values of 1.18 and 6.28 μm against HCT-116 and MCF-7 cell lines, respectively. The preliminary results indicated that the oxidation of C-19-hydroxyl group of andrographolide to corresponding carboxyl group and the subsequent esterification of the formed carboxylic acid led to considerable improvement in cytotoxicity against the cancer cells.

A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate/sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide/methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.