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Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3′,4':3,4]cyclohepta[1,2-d] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC50's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC50 value of 0.10 μM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments.

As extension of previous studies on polycyclic planar systems which synthetic approach and antiproliferative activity against leukemic cells (FLC, DRTL) were reported, now we became interested to test their antireplicative activity against human immunodeficiency virus since the incorporation of the pyrrole moiety has already led to several classes of non nucleoside reverse transcriptase inhibitors. For this purpose new and non new derivatives of the planar system pyrrolo[1,2-f]phenanthridine and their “non-rigid analogues” were chosen as model framework reaching in total to more than forty compounds variously functionalized. The need for the search of new anti-HIV agent is still pursued because of the increasing spread of the disease in spite of several prevention campaigns, and because of the rapid appearance of drug resistant viral strains which limits drug effectiveness. Among the current anti-HIV agents the reverse transcriptase inhibitors the Nevirapine and TIBO have an important clinical role. It is suggested that they interact with an allosteric site of the enzyme assuming a “butterfly conformation.” This type of conformation is proposed in our “non-rigid” analogue derivatives tested. Molecular modelling studies by using some physico-chemical descriptors (molecular volume, accessible surface area) evidenced good similarities when compared with planar derivatives and highly described substituted pyrroles and were found in good agreement with the docking studies performed by Ding et al, which proposed a receptor having a “butterfly shape region”. At the same time, the superimposition in the conformation of the minimum of energy between Nevirapine, some selected planar compounds and the corresponding non-rigid analogues showed a good geometric fit between the structures (RMS in the range 0.0270-0.0455). These data suggest that a lot of our derivatives could fit favourably in the same binding pocket. Biological screenings evidenced that only few derivatives showed a moderate selectivity against HIV-1, suggesting that even planar molecules having suitable size can inhibit virus replication probably interacting with the same receptor. Moreover, an interesting biological new data has emerged: a planar derivative showed unique properties being able not only to reduce the virus-induced cyto-pathogenecity, but also to stimulate the growth (20-35%) of the same lymphocytes. Considering that the stimulation of the lymphocytes cells can be a crucial factor in anti-AIDS therapy, this class of compounds can be considered for further developments of new candidates which join anti-AIDS and immuno-stimulant activity.