Neeraj Mahindroo

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.

Hedgehog-Gli Signaling Pathway Inhibitors as Anticancer Agents

Cancer drug discovery has undergone a paradigm change over the past few years, from predominantly cytotoxic agent-based therapy to therapy aimed at genetic and molecular targets, thanks to a growing understanding of the genes and pathways responsible for cancer initiation and progression and to new drug discovery technologies. The success of drugs like trastuzumab, imatinib, gefitinib, and erlotinib has demonstrated that the targeting of specific oncogenic signal transduction pathways can be clinically useful.1 One such pathway, the Hedgehog-Glioma-associated oncogene homolog zinc finger protein (Hh-Gli)a signaling pathway, has attracted drug discovery scientists for the past decade. Hh-Gli signaling plays an important role in the embryonic patterning and development of many tissues and somatic structures as well as maintaining and repairing mature tissues in adults.2-4 Uncontrolled activation of the Hh-Gli pathway has been implicated in several cancers, including medulloblastoma, rhabdomyosarcoma, melanoma, basal cell carcinoma, and breast, lung, liver, stomach, prostate, and pancreatic cancers. 2, 5-8 Inhibition of the aberrant Hh-Gli pathway (Figure 1) has thus emerged as an attractive target for anticancer therapy.9-11 One Hh pathway inhibitor has shown promising results in phase I clinical trials and is proceeding to phase II12 studies, and two other compounds have entered phase I clinical trials.13, 14 In this article, we review the medicinal chemistry efforts to identify and design inhibitors of Hh-Gli signaling and present a perspective of future developments in this dynamic field. We also present a brief overview of the role of Hh-Gli signaling pathway in normal development and cancer. Figure 1 Hedgehog pathway activators and inhibitors The hedgehog (Hh) gene was first identified during a search for embryonic lethal mutants of Drosophila melanogaster, which found that mutation of Hh resulted in altered segment patterning of the larva.15 Subsequently the gene was identified in many other invertebrates and vertebrates, including humans. Three mammalian counterparts of the Hh gene, termed Sonic hedgehog (Shh), Dessert hedgehog (Dhh), and Indian hedgehog (Ihh), were identified by combined screening of mouse genomic and cDNA libraries.16 Hh undergoes multiple processing events, including autocatalytic cleavage of the C-terminal domain combined with addition of a cholesterol moiety at the cleavage site, and an N-terminal palmitoylation, to generate the active ligand.17-19 The receptor of secreted Hh protein is the multipass transmembrane protein Patched (Ptch). Of the two vertebrate homologs of Ptch, Ptch1 and Ptch2, the role of Ptch1 is better understood. In the absence of Hh ligand, Ptch inhibits the activity of the downstream effector Smoothened (Smo). The binding of Hh inactivates Ptch, resulting in activation of Smo.20 In Drosophila, a complex of proteins comprising Fused (Fu), Suppressor of Fused (SuFu), and Costal-2 (Cos2) mediates signaling downstream of Smo and is aided by several kinases, such as protein kinase A (PKA), glycogen synthase kinase 3 (GSK3), and casein kinase 1 (CK1). Mammalian homologs of Fu and Cos2 have not yet been identified, suggesting that the signaling mechanisms differ in mammals and Drosophila. 21, 22 Several mammalian-specific kinases that are required for Shh signaling have been identified.23-25 These proteins modulate the function of Gli (Ci in Drosophila), the only transcription factor identified to date that operates directly downstream of Hh. The first vertebrate Gli gene to be discovered was human Gli1, which was amplified about 50-fold in a malignant glioma.26 Vertebrates have three Gli proteins (Gli1, Gli2 and Gli3), all of which have five highly conserved tandem zinc fingers, a fairly conserved N-terminal domain, several potential PKA sites, and a number of additional small conserved regions in the C-terminal end. Despite these similarities, the functions of the Gli subtypes differ. Both Gli2 and Gli3 contain activation and repressor domains. Consequently, in the absence of upstream Hh signal, full-length Gli3 and, to a lesser extent, Gli2, are constitutively cleaved to generate a truncated repressor form.27-29 Hh signaling inhibits this cleavage, resulting in full-length Gli2 and Gli3, which have activator function. Gli1, in contrast, does not undergo proteolytic cleavage and acts as a constitutive activator.27 The transcription of Gli1 gene is initiated by Hh and is also controlled by Gli3.27 Target genes of the Hh pathway other than Gli1 include Ptch, several Wnt and TGFβ superfamily proteins, cell cycle proteins such as cyclin D, and stem-cell marker genes such as NANOG and SOX2.30, 31 Investigators are now attempting to comprehensively identify the Gli1-target genes.32, 33

Structure-activity and crystallographic analysis of benzophenone derivatives-the potential anticancer agents.

Compounds 1-5, structurally related to combretastatin A-4 showed excellent cytotoxic activities against a panel of human cancer cell lines including multi-drug resistant cell lines. The X-ray three-dimensional structural analysis shows that proton donor in B ring may be required for cytotoxic activity, with intermolecular hydrogen bonding playing an important role.

Antitubulin agents for the treatment of cancer – a medicinal chemistry update

The antitubulin agents taxanes and Vinca alkaloids form the first-line of treatment in clinical oncology for many cancers. The crucial role of microtubules in cell division has made antitubulin agents the focus of research, with sustained efforts to find new agents and to improve the profile of known agents by overcoming multi-drug resistance (MDR) and improving the druggability. The present review updates the medicinal chemistry of antitubulin agents covering the patents and literature published from May 2002 to November 2005. The antitubulin agents have been broadly classified into microtubule-destabilising agents, microtubule-stabilising agents and kinesin-like spindle protein inhibitors. This review provides an insight into the diversity of the chemical classes with antitubulin mechanisms of anticancer activity.

Structure–Activity Relationship Studies of 3‐Aroylindoles as Potent Antimitotic Agents

The concise synthesis and structure–activity relationship (SAR) studies of 3‐aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the 3‐carbonyl linker. The SAR information revealed that the methoxy group of the B ring could be replaced with an electron‐donating group such as methyl (in compound 9) or N,N‐dimethylamino (in compound 13) while retaining both strong cytotoxic and antitubulin activities. The introduction of amide (compounds 30–33) and carbamate (compounds 34–37) functionalities at the N1 position of 8 gave analogues with potent antiproliferative activities. The cytotoxic potency of 8 was improved by replacing the carbonyl group with sulfide (compound 41) or oxygen (compound 43), indicating that the carbonyl moiety is important but not essential. The N,N‐dimethylamino derivative 13 not only displayed potent cytotoxicity and antitubulin activity, but also showed a markedly improved physicochemical profile relative to the parent compound.

A three-dimensional pharmacophore model for dipeptidyl peptidase IV inhibitors

Dipeptidyl peptidase IV (DPP-IV) is a valid drug target for type-2 diabetes and DPP-IV inhibitors have been proven to efficiently improve glucose tolerance. In our study, 3D pharmacophore models were generated using a training set of 22 DPP-IV inhibitors. The best model consisted of important chemical features and mapped well into the active site of DPP-IV. The model gave high correlation coefficients of 0.97 and 0.84 for the training set and the test set, respectively, showing its good predictive ability for biological activity. Furthermore, the pharmacophore model demonstrated the capability to retrieve inhibitors from database with a high enrichment factor of 42.58. All results suggest that the model provides a useful tool for designing novel DPP-IV inhibitors.

Erratum to ‘Structure–Activity and Crystallographic Analysis of Benzophenone Derivatives—the Potential Anticancer Agents’ [Bioorg. Med. Chem. Lett. 13 (2003) 101]†

Divison of Biotechnology and Pharmaceutical Research, National Health Research Insitutes, 9F, 161, Sec. 6, Min-Chiuan East Road, Taipei 114, Taiwan, ROC Division of Cancer Research, National Health Research Institutes, Taipei 115, Taiwan, ROC Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, ROC Department of Chemical Engineering, Kuang Wu Institute of Technology, Taipei 112, Taiwan, ROC Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan, ROC