It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

https://www.mdpi.com/1424-8247/13/1/8/pdf

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review.

Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets. 

/pdf/nitrogen-containing-heterocycles-as-anticancer-agents-a-2eis4t9i.pdf

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective

Molecular diversity of trimethoxyphenyl-1,2,3-triazole hybrids as novel colchicine site tubulin polymerization inhibitors.

Discovery of tertiary amide derivatives incorporating benzothiazole moiety as anti-gastric cancer agents in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.

Novel tertiary sulfonamide derivatives containing benzimidazole moiety as potent anti-gastric cancer agents: Design, synthesis and SAR studies.

We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

/pdf/structure-activity-relationship-studies-of-b-lactam-azide-2qfgssu9g5.pdf

Structure-Activity Relationship Studies of β -Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

The invention discloses a formononetin derivative comprising dithiocarbamate, and a preparation method and application of the formononetin derivative to antitumor drugs, and belongs to the field of pharmaceutical chemistry. The mother nucleus of formononetin is combined with a dithiocarbamate active unit to simply, efficiently and greenly synthesize the formononetin derivative comprising dithiocarbamate. The general molecular formula of the formononetin derivative comprising dithiocarbamate is shown in the description. The in vitro antitumor activity test of the compound indicates that the formononetin derivative has a certain effect of inhibiting multiple tumor cells of EC-109, MGC-803 and PC-3. Compared with the natural formononetin, the anti-prostate cancer activity of the formononetin derivative I-8 comprising dithiocarbamate is improved by 28 times, so that the formononetin derivative comprising dithiocarbamate is a candidate or a lead compound for further development, and is applied to the preparation of the antitumor drugs.

Formononetin derivative comprising dithiocarbamate, preparation method and application thereof to antitumor drugs

The invention discloses a preparation method of 3-chloromethyl oxacephem antibiotics parent nucleus and belongs to the technical field of drug synthesis. According to the invention, compound 1 is used as the raw material, and a three-step reaction is carried out to synthesize the 3-chloromethyl oxacephem framework (compound 4) which is defined in the description. Compared with the prior art, the synthesis route of the oxacephem antibiotics parent nucleus can be effectively shortened, the use of chlorine and heavy metal reagents is avoided, a light-shading device is not needed in industrial production, the post-treatment is convenient, the product yield is obviously improved, the cost is low, the green and environment-friendly effects are achieved, and therefore the competitiveness in scale industrial production is relatively strong.

Preparation method of 3-chloromethyl oxacephem antibiotics parent nucleus

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Structure-Activity Relationship Studies of β -Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Formononetin derivative comprising dithiocarbamate, preparation method and application thereof to antitumor drugs

Preparation method of 3-chloromethyl oxacephem antibiotics parent nucleus