We developed synthetic chemistry to access the marine alkaloid rigidins and over forty synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [3H]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have significant potential as new anticancer agents.

Privileged medicinal scaffolds based on the structures of tetra-and penta-substituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkyl-sulfonamido)-acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C and D in overall yields 61%, 58%, 60% and 53%, respectively. Of these, rigidins B, C and D were synthesized for the first time.Polysubstituted pyrroles are an important class of heterocycles that display diverse pharmacological activities. 1 Furthermore, they are useful building blocks in the synthesis of natural products and heterocyclic chemistry. Although a large number of new pyrrole syntheses, 2 including multicomponent reactions (MCRs), 3 have been reported in recent years, relatively few examples are known for the preparation of polysubstituted 2-aminopyrroles. 4 Aminopyrroles are not readily available through general pyrrole ringformation methods. At the same time the 2-aminopyrrole fragment is part of many different bioactive compounds and it is recognized as a privileged medicinal structure. Known bioactivities for this class of compounds include anti-inflammatory, 5 anticancer, 6 antiviral, 7 antifungal, 8 pesticidal, 9 radioprotective, 10 MEK inhibitory, 11 MK2 inhibitory, 12 FAK, KDR and Tie2 inhibitory, 13 PDE inhibitory, 14 anti-interleukin-6, 15 TNF-α production inhibitory, 16 and afferent pelvic nerve activity inhibitory. 17 Moreover, 2-aminopyrroles are precursors for the synthesis of purine analogs -pyrrolopyrimidines, pyrrolotriazines and pyrrolopyridines. [18][19][20][21][22][23][24] Previously, we described a novel method for the synthesis of multisubstituted pyrrolines using a multicomponent reaction of various N-(aryl-and alkylsulfonamido)-acetophenones with aldehydes and malononitrile (see Table 1 graphic). 27 While the reaction is regioselective, it is not stereoselective and gives mixtures of cis and trans 2-pyrrolines, which are not easily separable. Utilizing this methodology as a starting point, we developed a new muticomponent one-pot method for the synthesis of tetra-and penta-diversely substituted 2-aminopyrroles. In addition, we utilized the new method for a short total synthesis of alkaloids rigidins A, B, C and D.Penta-substituted 2-aminopyrroles A 1-17 were prepared by a multicomponent reaction of N-(aryl-, hetaryl-and alkylsulfonamido)-acetophenones, aldehydes and cyanoacetic acid derivatives in acetonitrile, followed by oxidation with DDQ in one pot (Table 1). This threecomponent process works well for any tested combination of aliphatic, aromatic (including sterically hindered or heteroaromatic) aldehydes and malononitrile, cyanoacetamide or ethyl cyanoacetate. Because of the lower reactivity of the intermediate Knoevenagel products of cyanoacetamide or ethyl cyanoacetate, the reactions were sluggish in acetonitrile (A 16 and A 17 ). In these cases the pyrrolines were obtained in ethanol, the solvent was the...

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine’s natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to proapoptotic stimuli. Bulbispermine, haemanthamine and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited noteworthy growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion and displayed comparable potencies in both cell types, indicating that apoptosis induction is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from the rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis resistant cancers and glioblastoma in particular.

A novel reaction of indole with aryldiazonium salts leading to the formation of 2-aryl-3-(arylazo)indoles was discovered. The products were found to possess potent anti-MRSA and anti-LLVRE activities. The SAR studies indicate that the potentially metabolically labile azo functionality can be replaced with ether oxygen and thioether sulphur atoms without any loss of activity.

The aryl hydrocarbon (Ah) receptor undergoes a ligand-dependent transformation to a heteromeric structure which has the ability to bind DNA sequence-specifically with high affinity. By this mechanism, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related xenobiotics modify gene expression. We observed that transformation was inhibited in vitro by the presence of ribonuclease A (RNAase) during incubation of rat hepatic cytosol with TCDD. This effect was detected as a decreased ability of the TCDD-receptor complex to bind to calf thymus DNA covalently linked to Sepharose, and to a dioxin-responsive enhancer which is upstream of the cytochrome P450IA1 structural gene. RNAase had no effect on previously transformed TCDD-receptor complexes. These observations indicated that RNAase acted during ligand binding and/or transformation of the Ah receptor. Saturation binding analyses demonstrated that RNAase decreased the receptor affinity for TCDD without changing the total number of binding sites. RNAase also inhibited transformation of the TCDD-bound, partially purified, untransformed, receptor. Thus RNAase does not interfere with ligand binding, but inhibits the subsequent transformation of the receptor monomer to the heteromeric, transcriptionally active, form.