Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads

Leverett, Carolyn A.; Sukuru, Sai Chetan K.; Vetelino, Beth C.; Musto, Sylvia; Parris, Kevin; Pandit, Jayvardhan; Loganzo, Frank; Varghese, Alison H.; Bai, Guoyun; Liu, Bin; Liu, Dingguo; Hudson, Sarah P.; Doppalapudi, Venkata Ramana; Stock, Joseph R.; O’Donnell, Christopher J; Subramanyam, Chakrapani

doi:10.1021/acsmedchemlett.6b00274

Cited by 34 publications

(18 citation statements)

References 18 publications

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“…New derivatizations at C-terminal Tup showed broad tolerance with no loss of activity, enabling more opportunities to conjugate to biomolecules and receptor ligands [80]. Another issue that arose during ADC conjugation of tubulysins to trastuzumab is the metabolism of C 11 acetate in vivo, inactivating the payload [81,82]. The problem was solved replacing the acetate ester by a more inert functionality to esterases like carbamates, retaining the activity.…”

Section: Linear Peptidesmentioning

confidence: 99%

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

Ramos-Inza¹,

Aydillo²,

Sanmartín³

et al. 2020

Heterocycles - Synthesis and Biological Activities

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Currently, cancer is one of the major health problems of the human population and prominent cause of death. Thiazole ring has demonstrated many pharmacological activities including anticancer. This scaffold has been found alone or incorporated into the diversity of therapeutic active agents such as tiazofurin, dasatinib, and bleomycin, which are well-known antineoplastic drugs. Recently, most of the compounds isolated from natural sources containing thiazole moiety exhibit notable cytotoxicities and present antitumor potential. In this context, several structural changes have been made in the original structure, such as the incorporation of different substituents or the fusion with other carbo-and heterocycles, in order to increase the antitumoral potency. Related to mechanism of action of these derivatives, some of them act through kinase modulation, polymerization inhibition of microtubule, pro-matrix metalloproteinase activation, signal transducer activation of transcription 3, histone deacetylase inhibition, etc.

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Section: Linear Peptidesmentioning

confidence: 99%

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

Ramos-Inza¹,

Aydillo²,

Sanmartín³

et al. 2020

Heterocycles - Synthesis and Biological Activities

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“…Several ligands (Figure A), natural peptides, or analogs (eg dolastatins, auristatins, and tubulysins), have subsequently been structurally characterized bound to the vinca site. They climb H7 and extend towards H1 and contact the β subunit further than vinblastine, thus leading to very potent tubulin polymerization inhibitory activity and cytotoxicity.…”

Section: Tubulin As a Targetmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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Tubulin, the microtubules and their dynamic behavior are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal drug targets. Sulfonamides are exemplary drugs with applications in the clinic, in veterinary and in the agrochemical industry. This review summarizes the actual state and recent progress of both fields looking from the double point of view of the target and its drugs, with special focus onto the structural aspects. The article starts with a brief description of tubulin structure and its dynamic assembly and disassembly into microtubules and other polymers. Posttranslational modifications and the many cellular means of regulating and modulating tubulin's biology are briefly presented in the tubulin code. Next, the structurally characterized drug binding sites, their occupying drugs and the effects they induce are described, emphasizing on the structural requirements for high potency, selectivity, and low toxicity. The second part starts with a summary of the favorable and highly tunable combination of physical-chemical and biological properties that render sulfonamides a prototypical example of privileged scaffolds with representatives in many therapeutic areas. A complete description of tubulin-binding sulfonamides is provided, covering the different species and drug sites. Some of the antimitotic sulfonamides have met with very successful Med Res Rev. 2019;39:775-830. wileyonlinelibrary.com/journal/med © 2018 Wiley Periodicals, Inc. | 775applications and others less so, thus illustrating the advances, limitations, and future perspectives of the field.All of them combine in a mechanism of action and a clinical outcome that conform efficient drugs. K E Y W O R D S molecular mechanisms, sulfonamides, tubulin binding drugs, tubulin binding sites 1 | INTRODUCTION Drugs targeting tubulin and the microtubules (tubulin binding drugs [TBDs]) are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal agents with applications in the clinic, in veterinary and in the agrochemical industry. Recently, the combination of computational methods, medicinal chemistry, biochemistry, structural biology, and cell biology is starting to unravel the intricacies of tubulin binding drugs and of the microtubules themselves, thus paving the way towards new and better TBDs. New methodological advances such as the high resolution cryo-electron microscopy, the imaging of individual microtubule dynamics, and the achievement of recombinant tubulin, altogether with more established methodologies for the study of the microtubules have combined to provide a sharper view of the structure and function of these essential cell components and their interactions with clinically important drugs. The sulfonamides are a prototypical example of privileged scaffolds, with representatives in many therapeutic areas, due to a combination of favorable and highly tunable physical-chemical and biological properties. The early discovery of the dinitroaniline herbicides, and mainly the seminal discovery o...

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“…[80] Angewandte Chemie Reviews candidate ADCs. [85] These include anthramycin, halichondrin B, duocarmycin SA, tubulysin D, and N 14 -desacetoxytubulysin H, shishijimicin A, uncialamycin, disorazole B 1 ,a ziridinyl epothilones, a-amanitin, aplyronine D, and thailanstatin A. Below we highlight the total syntheses of these natural products and anumber of their analogues.…”

Section: Total Synthesis Of Natural Products and Their Analogues As Pmentioning

confidence: 99%

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

Nicolaou

Rigol

2019

Angew Chem Int Ed

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With a number of antibody–drug conjugates (ADCs) approved for clinical use as targeted cancer therapies and numerous candidates in clinical trials, the field of ADCs is emerging as one of the frontiers in biomedical research, particularly in the area of cancer treatment. Chemists, biologists and clinicians, among other scientists, are partnering their expertise to improve their design, synthesis, efficacy and precision as they strive to advance this paradigm of personalized and targeted medicine to treat cancer patients more effectively and to expand its scope to other indications. Just as Alexander Fleming's penicillin, and the myriad other bioactive natural products that followed its discovery and success in the clinic, ignited a revolution in medicine after the Second World War, so did calicheamicin γ1I, and other highly potent naturally occurring antitumor agents, play a pivotal role in enabling the advent of this new paradigm of “biological‐small molecule hybrid” medical intervention. Today there are four clinically approved drugs from the ADC paradigm, Mylotarg, Adcetris, Kadcyla and Besponsa, in order of approval, the first and the last of which carry the same calicheamicin γ1I‐derived payload. Covering oncological applications, and after a brief history of the emergence of the field of antibody–drug conjugates triggered more than a century ago by Paul Ehrlich's “magic bullet” concept, this Review is primarily focusing on the chemical synthesis aspects of the ADCs multidisciplinary research enterprise.

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Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads

Cited by 34 publications

References 18 publications

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

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