Covering: up to December 2011 This review highlights the potential of natural and semisynthetic ursane-type triterpenoids as candidates for the design of multi-target bioactive compounds, with focus on their anticancer effects. A brief illustration of the biosynthesis, sources, and general biological effects of the main classes of naturally occurring pentacyclic triterpenoids (PTs) are provided.

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

Asiatic acid (AA) is a pentacyclic triterpenoid with recognized anticancer properties. Structural modification of AA may afford derivatives with improved anticancer potency. Hence, in this paper, a series of new lactol and A-nor AA derivatives were prepared, and their antiproliferative activities against several human cancer cell lines and a non-tumoral fibroblast cell line (BJ) were tested. Among all the derivatives tested, compound 24 proved to be the most active compound, with IC₅₀ values ranging from 0.11 μM to 0.65 μM for cancer cell lines. The molecular mechanisms underlying its antiproliferative activity were further investigated using the HeLa cell line. Our results showed that treatment of HeLa cells with compound 24 led to cell-cycle arrest at the G0/G1 phase, which was associated with an upregulation of p21^cip1/waf1 and p27^kip1 and a downregulation of cyclin D₃. Moreover, compound 24 induced apoptotic HeLa cell death via the activation of caspase-9, caspase-8, and caspase-3. The downregulation of the Bcl-2 and Bid proteins and the upregulation of the Bax protein suggest that the mitochondrial pathway is activated during the apoptotic process.