Natural products (secondary metabolites; naturally occurring small organic molecules) continue to play a pivotal role in modern drug discovery since they are superior new drug leads compared with purely synthetic compounds (hit rates of ~0.3% vs. <0.001%, respectively)[1]. Interestingly however, in most cases the active ingredient of the end-product (drug) is not a natural product but rather a semisynthetic modification or a totally synthetic compound with a natural product-inspired pharmacophore. This highlights the importance of modern synthetic organic chemistry in the exploitation of natural products. In return, natural products, with their diverse and often complex structures and important biological activity, historically define the state of the art of organic chemistry. Today, they continue to drive basic research in synthetic organic chemistry (for the discovery and validation of new methods and strategies)[2] and are valuable tools for Chemical Biology[3] (i.e. the exploration of biological systems using chemistry techniques).

In this context and aiming to facilitate further exploitation of bioactive natural products, objectives of this group are:

  • The total synthesis of natural products with important biological activities.
  • The establishment of Structure / Activity Relationships.
  • The design, synthesis and study of designed analogues thereof.
  • The training of young researchers in the “Art and Science” of Natural Products Synthesis.

In parallel, the expertise of the team in the design and synthesis of complex organic molecules is exploited for:

  • The preparation of organic molecules with possible technological applications (e.g. photoresist etch enhancement additives, linkers for the preparation of polymers) or molecules with interesting supramolecular behavior.

Representative recent activities

Terpenes with selective anticancer activities: Stemming from the interest of our group in the synthesis and study of natural products with important biological activities and following recent past accomplishments in this area (e.g. total synthesis of Scyphostatin[4], a potent and selective N-SMase inhibitor; the first enantioselective total synthesis of Laurenditerpenol[5], a marine diterpene that targets hypoxic signaling in tumor cells), a new research project focusing on the natural product Taepeenin D, a novel Hedgehog/GLI inhibitor, and related furanoditerpenoids that could target cancer stem cells (CSCs) has been initiated.

The Hedgehog (Hh) signaling pathway is one of the pathways that control embryonic patterning and cellular proliferation and differentiation. However, its abnormal activation has been linked with the occurrence of basal cell carcinoma and meduloblastoma while several other tumors (such as cancers of the skin, brain, lung, pancreas, digestive tract, prostate) are co-dependent on Hh signaling. Moreover, recent evidence suggests that Hh signaling is important for the self-renewal of cancer stem cells in pancreatic cancer, glioblastoma, multiple myeloma as well as in chronic myeloid leukemia. Thus, inhibition of Hh pathway has become an attractive strategy in anticancer therapy and several related clinical trials are underway[6].

Taepeenin D is a cassane-type diterpenoid originally isolated from Caesalpinia crista that has been identified as a constituent of Acacia pennata with significant Hh/Gli-mediated transcription inhibitory activity (IC50 1.6 μM) and selective cytotoxicity against cancer cells with increased Hh signaling levels (IC50 3.2-3.4 μM)[7]. Synthetic studies directed towards the total synthesis of this natural product were initiated. In parallel, a series of related analogues were prepared exploiting abietic acid (a readily available starting material; main constituent of rosin) and evaluation of their activity as Hh/Gli inhibitors has allowed the identification of important structural features (SAR studies)[8].


1. J.W.H. Li, J.C. Vederas, Science 2009, 325, 161; G.M. Cragg, et al., Chem. Rev. 2009, 109, 3012; D.J. Newman, G.M. Cragg, J. Nat. Prod. 2007, 70, 461.

2. K.C. Nicolaou, S.A. Snyder, Classics in total synthesis II, WILEY-VCH Verlag GmbH & Co., Weinheim, Germany, 2003; K.C. Nicolaou, E.J. Sorensen, Classics in total synthesis, VCH Publishers, Inc., New York (USA), 1996.

3. Editorial, “The state of the art of chemical biology”, ChemBioChem 2009, 10, 16.

4. E.N. Pitsinos,  N. Athinaios, Z. Xu, G. Wang, E.-I. Negishi, Chem. Commun. 2010, 46, 2200.

5. E.N. Pitsinos, N. Athinaios, V.P. Vidali, Org. Lett. 2012, 14, 4666.

6. T.N. Trinh, et al. Med. Chem. Commun. 2014, 5, 117; D. Amakye, et al. Nat. Med. 2013, 19, 1410.

7. Y. Rifai, et al.,  J. Nat. Prod. 2010, 73, 995.

8. M. Chatzopoulou, A. Antoniou, E.N. Pitsinos, M. Bantzi, S.D. Koulocheri, S.A. Haroutounian, A.G. Giannis, Org. Lett. 2014, 16, 3344.