Structural Basis of Noscapine Activation for Tubulin Binding.

Noscapine is a natural alkaloid that is used as an antitussive medicine. However, it also acts as a weak anticancer agent in certain in vivo models through a mechanism that is largely unknown. Here, we performed structural studies and show that the cytotoxic agent 7A-O-demethoxy-amino-noscapine (7A-aminonoscapine) binds to the colchicine site of tubulin. We suggest that the 7A-methoxy group of noscapine prevents binding to tubulin due to a steric clash of the compound with the T5-loop of α-tubulin. We further propose that the anticancer activity of noscapine arises from a bioactive metabolite that binds to the colchicine site of tubulin to induce mitotic arrest through a microtubule cytoskeleton-based mechanism.

Natural products in medicine: transformational outcome of synthetic chemistry.

This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and ß-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives.

Tubulin binding, protein-bound conformation in solution, and antimitotic cellular profiling of noscapine and its derivatives.

Noscapine and its 7-hydroxy and 7-amino derivatives were characterized for their binding to tubulin. A solution NMR structure of these compounds bound to tubulin shows that noscapine and its 7-aniline derivative do not compete for the same binding site nor does its small molecule crystal structure match its tubulin-bound conformation. These compounds were also tested for their antiproliferative effects on a panel hepatocellular carcinoma cell lines.

Investigation of 4-piperidinols as novel H3 antagonists.

Compounds containing a substituted 4-piperidinol core have been found to be potent antagonists of the human H(3) receptor. The compounds exhibited up to a 60-fold preference for inhibiting the human H(3) receptor over the mouse and showed a low binding affinity for the hERG channel.

Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole.

The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-activity relationships.

A new histamine H3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based on a previously identified conessine-based H3R antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H3 K(i) of 0.54 nM, rat H3 K(i) of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).

Identification of novel and improved antimitotic agents derived from noscapine.

Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.

Discovery of S-phase arresting agents derived from noscapine.

Analogues of the natural product noscapine were synthesized, and their potential as antitumor agents were examined. The discovery of a novel regio- and stereoselective O-demethylation led to the synthesis of several O-alkylated analogues that induced an unexpected S-phase arrest of mammalian cells. Compound 4a was the most potent analogue inhibiting cell proliferation at an EC(50) of 1.9 microM.

The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors.

Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date.