R-3 Repository :: Browsing by Author "Nicolaou, Kyriacos C."

Browsing by Author "Nicolaou, Kyriacos C."

Now showing 1 - 13 of 13

Derivatives of thailanstatin A, methods of treatment and methods of synthesis thereof
(2023-02-21) Nicolaou, Kyriacos C.; Rhoades, Derek; Kumar, Soundarapandian M.; Pattanayak, Manas R.; Lamani, Manjunath; Rice University; William Marsh Rice University; United States Patent and Trademark Office
In one aspect, the present disclosure provides analogs of thailanstatin of the formula wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein.
Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
(2021-01-12) Nicolaou, Kyriacos C.; Lu, Min; Mandal, Debashis; Gangwar, Sanjeev; Chowdari, Naidu S.; Poudel, Yam B.; Rice University; BRISTOL-MYERS SQUIBB COMPANY; The Scripps Research Institute; United States Patent and Trademark Office
In one aspect, the present disclosure provides new analogs of uncialamycin. The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates which may be used to treat cancer or another disease or disorder.
Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
(2017-10-03) Nicolaou, Kyriacos C.; Lu, Min; Mandal, Debashis; Gangwar, Sanjeev; Chowdari, Naidu S; Poudel, Yam B.; Rice University; United States Patent and Trademark Office
In one aspect, the present disclosure provides new analogs of uncialamycin of formulae (I) and (II). The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates comprising the compounds of formulae (I) and (II).
Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
(2019-03-19) Nicolaou, Kyriacos C.; Lu, Min; Mandal, Debashis; Gangwar, Sanjeev; Chowdari, Naidu S.; Poudel, Yam B.; Rice University; The Scripps Research Institute; Bristol-Myers Squibb Company; United States Patent and Trademark Office
In one aspect, the present disclosure provides new analogs of uncialamycin. The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates which may be used to treat cancer or another disease or disorder.
Desacetoxytubulysin H and analogs thereof
(2020-10-20) Nicolaou, Kyriacos C.; Vourloumis, Dionisios; Yin, Jun; Erande, Rohan; Mandal, Debashis; Klahn, Phillipp; Rice University; United States Patent and Trademark Office
"In one aspect, the present disclosure provides tubulysin analogs of the formula (I) wherein R1, R2, R3, R4, X1, X2, X3, and A1 are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. "
Developing an Enzyme Toolbox for Anti-Tumor Natural Product Biosynthesis
(2016-04-21) Wang, Fengbin; Phillips, Jr., George N.; Nicolaou, Kyriacos C.
Natural products, known as chemical compounds or substances produced by living organisms, are arguably the most important players in revolutionizing modern medicine. To date, natural products remain the best source of drug leads, including penicillin, streptomycin, artemisinin and others. However, one of the difficulties of natural product-based drug discovery is the structural derivatization. The traditional chemical modification methods often require multiple protection and deprotection steps for the large variety of functional groups, making the process laborious and problematic. A promising alternative approach to produce natural product derivatives is utilizing biosynthesis enzyme toolbox; for example, enzyme-based "glycol-randomization" and "alkyl-randomization" can dramatically expand diversities of important anti-cancer natural products. In my thesis work, I characterized seven biosynthesis enzymes (including sugar aminotransferase WecE, CalS13, AtmS13, glycosyltransferase SsfS6, OleD, methionine adenosyltransferase sMAT and methyltransferase DnrK) by X-ray crystallography. The structural characterizations and protein engineering of those enzymes lead to successfully expand the glyco/alkyl libraries, as well as to broaden the glyco/alkyl installation processes. These discoveries and enzyme toolbox developments are directly applicable to future drug discovery for cancer, and can be utilized as blue print to further understand the essential role of glycosylation and methylation in biology.
Epothilone analogs, methods of synthesis, methods of treatment, and drug conjugates thereof
(2020-12-29) Nicolaou, Kyriacos C.; Rhoades, Derek; Wang, Yanping; Totokotsopoulos, Sotirios; Rice University; United States Patent and Trademark Office
"In one aspect, the present disclosure provides epothilone analogs of the formula (I) wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, drug conjugates with cell targeting moieties of the compounds are also provided. "
Preparation and biological evaluation of viridicatumtoxin analogs
(2018-09-04) Nicolaou, Kyriacos C.; Hale, Christopher R.H.; Nilewski, Christian; Ioannidou, Heraklidia; El Marrouni, Abdellatif; Rice University; United States Patent and Trademark Office
"In one aspect, the present invention provides novel derivatives of viridicatumtoxin of the formula wherein the variables are as defined herein. The application also provides compositions, methods of treatment, and methods of synthesis thereof. "
Synthesis of anticancer agents: 15-deoxy-15-fluoro-Δ12-prostaglandin J3 and gukulenin monomeric units
(2017-11-20) Yu, Ruocheng; Nicolaou, Kyriacos C.
The prostaglandins (PGs) are a class of natural products that have enjoyed unparalleled popularity among the chemical and biological community over the past century. The diverse endogenous functions of these fatty-acid-derived metabolites have provoked the pursuit of their chemical synthesis, culminating in the laboratory production of various natural and designed prostanoids, and the development of several landmark synthetic methodologies. Among the large family of PGs, a subclass known as the alkylidene-cyclopentenone prostaglandins (acyPGs) has been increasingly recognized for their prominent anticancer activities. In particular, Δ12-prostaglandin J3 (Δ12-PGJ3), a recently added member of the family, was reported to be effective in the in vitro and in vivo eradication of leukemia stem cells (LSC). This anti-LSC potency of Δ12-PGJ3 might represent a new solution in combating cancer recurrence, and therefore warrants systematic investigation into its structure–activity relationship (SAR). Thus, in Chapter 1, we described the synthesis of two key structural components of Δ12-PGJ3 — the cyclopentenone fragment (via a novel chiral lactone synthon), and the β-siloxyaldehyde fragment (via an asymmetric Keck allylation). The developed synthesis has enabled the preparation of dozens of analogs, including 15-deoxy-15-fluoro-Δ12-PGJ3 through a late-stage deoxyfluorination strategy. Biological evaluation of the synthesized compounds revealed that this “OH F” exchange at C15 was moderately beneficial for cytotoxicity improvement, presumably as a result of the increased lipophilicity and metabolic stability of the fluorinated analog. Chapter 2 describes our synthesis toward bis-tropolone cytotoxin gukulenin A. Historically, tropolone and its derivatives have been studied for their antitumor effects; and, as potent metal chelators, these aromatic structural motifs also carry great potential in material science and ligand development. However, research into tropolone-containing compounds has been hampered by their capricious chemical behavior and the inefficiency in derivatizing the aromatic backbone. In our quest toward the total synthesis of gukulenin A, we pioneered a “sequential tropolone functionalization” strategy in which the peripheral substituents were successively introduced in a regioselective manner. Our synthesis has not only furthered our knowledge in tropolone chemistry, but also provided a modular platform for the rapid generation of gukulenin analogs.
Total synthesis of shishijimicin A and analogs thereof
(2020-03-17) Nicolaou, Kyriacos C.; Li, Ruofan; Lu, Zhaoyong; Sohn, Te-ik; Woods, James; Pitsinos, Emmanouil N.; Rice University; United States Patent and Trademark Office
In one aspect, the present disclosure provides shishijimicin analogs of the formula: wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, antibody drug conjugates of the compounds are also provided.
Total synthesis of shishijimicin A, design, synthesis and biological evaluation of analogues thereof, and total synthesis and full structural elucidation of namenamicin
(2018-08-31) Li, Ruofan; Nicolaou, Kyriacos C.; Kurti, Laszlo; Farach-Carson, Mary C.
Enediyne natural products possessing both sophisticated chemical structures and outstanding bioactivities have received intensive attentions from chemical and biological communities since their first discovery made in 1960s. The isolations of these unusual naturally occurring substances have provoked tremendous efforts from interdisciplinary areas, culminating in comprehensive understandings and implementations on fermentative production, cytotoxicity, structural elucidation, mechanism of action, biosynthesis and total synthesis. Shishijimicins A–C and namenamicin are recently discovered marine-originated 10-membered ring enediyne natural products that render subnanomolar to picomolar levels of antibacterial and antitumor potencies. While these properties are highly desired in the targeted cancer therapies, such pharmaceutical applications are largely hampered by their scarce natural sources, which led to hitherto very limited understandings on these enediyne siblings. As a counterpart to the natural producer, chemical synthesis has long been valued for its potential of providing not only naturally existing materials, but also structurally modified analogues thereof, the latter being essential for the structure–activity relationship (SAR) studies. Therefore, in Chapter 1, we disclosed our first total synthesis of shishijimicin A, featuring a practical and scalable construction of its disaccharide domain by employing glycal glycosidation, β-carboline C–H functionalization, and lithio-β-carboline–aldehyde coupling reactions. The established synthetic methods and strategies have enabled the generation of an array of shishijimicin A analogues with various degree of chemical modifications as described in Chapter 2. The biological evaluations of the latter revealed several tolerable and intolerable structural changes with regards to the cytotoxic potencies, resulting in a graphic SAR on shishijimicin A. An intermediate en route to the total synthesis of shishijimicin A was diverted to the trisaccharide domain of namenamicin by utilizing modern glycosidation methods, which also gained its success in the final coupling with the enediyne warhead and led to, as presented in Chapter 3, the first syntheses of both 7′-epimers of namenamicin. The mysterious stereogenic center at 7′ position of natural namenamicin was unequivocally assigned by 1H NMR analysis on the rigidified polycyclic compounds. Additionally, the implemented semi-pinacol rearrangement within the synthesis of the methylthio sugar fragment has validated the use of 2-deoxy-ribofuranoside as a precursor of 2-deoxy-hexose through a ring expansion strategy, expanding our knowledge and synthetic toolbox in the carbohydrate synthesis.
Total synthesis of trioxacarcin DC-45-A2 and preparation of trioxacarcin analogs
(2021-01-26) Nicolaou, Kyriacos C.; Cai, Quan; Rice University; United States Patent and Trademark Office
"In one aspect, the present invention provides novel derivatives of trioxacarin analogs of the formula (I) wherein the variables are as defined herein. The application also provides compositions, methods of treatment, and methods of synthesis thereof. "
Tubulysin analogues as anticancer agents and payloads for antibody-drug conjugates and methods of treatment therewith
(2022-03-15) Nicolaou, Kyriacos C.; Erande, Rohan Diliprao; Vourloumis, Dionisios; Pulukuri, Kiran Kumar; Rigol, Stephan; Rice University; United States Patent and Trademark Office
In one aspect, the present disclosure provides tubulysin analogs of the formula (I) wherein the variables are as defined herein. In another aspect, the present disclosure also provides methods of preparing the compounds disclosed herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of use of the compounds disclosed herein. Additionally, drug conjugates with cell targeting moieties of the compounds are also provided.

Browsing by Author "Nicolaou, Kyriacos C."

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