Mini Reviews in Medicinal Chemistry - Volume 7, Issue 12, 2007

Combretastatin A-4 (CA-4) is one of the most potent antimitotic and antiangiogenic agents of natural origin. It has displayed potent antitumor effect in a wide variety of preclinical tumor models. Till date various CA-4 analogs have been synthesized and evaluated for anticancer activity. This review is an attempt to compile the medicinal chemistry of various synthesized CA-4 analogs.

We aim from this review to stimulate further research in this area by providing a description of the different types of inhibitors containing heparin mimetic molecules that have recently been reported and data on their biological activity. Molecules that mimic heparin and bind to heparin-binding growth factors are important building blocks for synthetic biomaterials. Different types of synthetic mimics of the biological properties of heparin have been prepared including high molecular weight compounds or small molecule mimics. Peptide-based mimics of heparin functionality are limited and because of their low degree of sulfation, they are natural targets as heparin mimics. Aromatic sulfonamide derivatives exhibit a range of bioactivities and a novel angiogenesis inhibitor (E 7820) is used as a TF model for screening assay. The anticoagulant activity of the known heparin pentasaccharide sequence prompted synthetic efforts aimed at the procurement of this structure as well as a host of related sequences. Chemical modification of the natural or synthetic heparin increased factor activation of AT III Xa affinity. A variety of non-peptide non-saccharides inhibitors as antiangiogenesis therapies directed against the VEGFR kinase are a promising and well-validated therapeutic approach under active evaluation of their safety and efficacy in multiple clinical trials. These low molecular weight modulators could be useful tools for biologists and may have potential as drugs or as leads for drug development.

Lantibiotics are ribosomally synthesised, post-translationally modified antimicrobial peptides that exhibit activity against a wide-range of Gram positive bacteria. During the last decade a number of two-peptide lantibiotics, i.e. lantibiotics that function optimally as a consequence of the synergistic activity of two peptides, have been identified, six of which (lacticin 3147, staphylococcin C55, plantaricin W, Smb, BHT-A and haloduracin) are closely related. It has been established in at least one instance, i.e. lacticin 3147, that these are extremely potent antimicrobials, which are active at nanomolar concentrations against a number of microorganisms, exhibit activity against multidrug resistant nosocomial pathogens such as MRSA and VRE and significantly, to date the development of significant levels of resistance has not been apparent. Given the similarity between lacticin 3147 and related two-peptide lantibiotics, it is likely that they too possess similarly beneficial traits and thus could potentially have medical and veterinary applications. In addition to discussing these aspects of two-peptide lantibiotic reasearch, this review will focus on new developments in this area pertaining to studies elucidating the mechanism of action of these antimicrobials, the use of bioengineering to reveal the location of essential and variable domains therein and the potential for the use of in vivo and in vitro engineering to create derivatives with even greater activities against specific target organisms.

There are several tetraspanins present in platelets including CD9, CD151, TSSC6, and CD63. Recent studies in knockout mouse models have revealed that CD151 and TSSC6 are physically and functionally involved in regulation of the ‘outside-in’ signalling properties of the major platelet integrin, integrin αIIbβ3 and thrombus stability in vivo.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 16 NCEs marketed in 2006.

Bacterial drug resistance against antimicrobial agents is a prevalent and central worldwide impasse. Infections with resistant organisms lead to adverse clinical outcomes, increased mortality, and are costly to healthcare systems. Several infectious diseases are initiated by the binding of pathogenic lectins to host cells glycoconjugates. The molecular understanding of these adhesion phenomena is crucial and presents promising new alternatives compared to traditional antibiotic therapies. Glycans or glycan mimetics could be used to inhibit the initial recognition events leading to adhesion and colonization of host tissues by pathogens. The bladder and urothelial lining are widely covered by cell surface glycoproteins bearing the required carbohydrate ligands responsible for the adhesion phenomena. However, when these interactions are measured on a per saccharide basis, they are generally too weak (mM) for the design of beneficial inhibition therapies. The interactions between microbial pathogens and host cells are often governed by polyvalent and overall strong avidities. To overcome this drawback, glycobiologists have design a new family of well-defined small macromolecules, called glycodendrimers that can successfully address this issue. This review will provide a brief introduction on glycodendrimers and detailed descriptions of design and applications of mannosylated inhibitors against fimbriated type 1 E. coli.