Small natural molecules represent an irreplaceable tool in the search for new agents and new directions in medicinal chemistry. In the cancer treatment area, the 79.8% of the new chemical entities approved for drug use from 1981 to 2006 were registered as naturally derived or inspired. The organic synthesis of natural product analogs of varying degrees of structural complexity is a powerful way of providing new drugs, improving ADME (Absorption, Distribution, Metabolism, Excretion) properties, fighting drug resistance and performing SAR (Structure-Activity Relationship) studies. The current project concerns the joint use of a synthetic methodology recently developed at the host group and of in silico modeling, for the synthesis of vinca alkaloids analogs. The vinca alkaloids and their analogs are mainstays of cancer chemotherapy, as they are able to bind tubulin and interfere with microtubule formation in mitosis, however the structural diversity of this group of drugs is very poor, with scarce divergence from the original natural products. The potential of the planned approach consists in the possibility of generating natural products analogs with key differences in the core structure, that are unprecedented in respect to “state-of-the-art” analogs syntheses and are not accessible through derivatization of the natural products or modification of their biosynthetic pathway. The newly synthesized chemical entities will then be examined both for their bioactivity (as anticancer agents) and for their pharmacological profile in collaborations with leading experts. The project presented herein merges Organic Chemistry, Biology and Pharmacology in a multidisciplinary quest that will certainly represent a high-quality contribution to cancer research in Europe and may be the basis for the discovery of a new generation of antitumor drugs.