Curing Cancer via Tyrosine Kinase Inhibitors, Schering Corp. & Tulane U.

Based on the findings of Krebs & Hunter that (protein-phosphorylating) tyrosine kinases drive both normal and oncogenic cell growth, as well as the mathematical modeling of enzyme phosphorylation-dephosphoryalation cascades of Schacter, Chock & Stadtman, selective inhibitors of oncogenic tyrosine kinases as drugs capable of precisely unraveling human carcinogenesis were proposed.  An invented two-step synthesis of potential tyrosine-kinase inhibitors was also published.  This research could not be pursued, but, a decade later, at Ciba-Geigy, Gleevec, a tyrosine-kinase inhibitor unraveling chronic myelogenous leukemia was quickly invented and FDA approved. Gleevec relatives are now in development in numerous institutions as cures or treatments of numerous cancers. 

Fast Drug-discovery via Invented, Nobel-prize-auguring Chemistry, Schering

The direct transformation of one biologically-active molecule to another is a powerful drug discovery tool.  However, drastic, general, chemical transformations are rare, as harsh reaction conditions, a frequent requirement, destroy molecules. This lack drove the invention of chemical reactions, driven by palladium-coupling chemistry, which precisely and drastically transform complex molecules, enabling fast drug-discovery. For example, these reactions transform tyrosine subunits in polypeptides, transforming tyrosine-kinase substrates to potential inhibitors useful in anticancer drug discovery, dopamine-receptor agonists to antagonists useful in antipsychotic drug discovery, etc.  They also change enzyme active-sites, enabling investigations of how enzymes work as well as constructions of new, useful enzymes.  Variants of these reactions for simpler (non-polypeptidic) organic molecules were awarded the 2010 Nobel Prize.  These reactions have also been driving drug discovery in industry, including Novartis (present owner of Gleevec), BASF, SmithKline Beecham, Sankyo, Hoffman-La Roche, Isis, Pfizer, Squibb, Chesebrough-Pond, Warner Lambert, Metabasis Therapeutics. 

Super-acid Chemistry Without Acid, U. of Chicago & Rockefeller U.

During studies on the total synthesis of a super-anticancer maytansinoid, a question arose: "How does one perform super-acid chemistry without acid?"  An answer was sought in the paradoxical world of enzymes, which easily transcend environmental constraints to perform seemingly impossible chemistry, e.g., strong-base or acid chemistry at neutral pH.  Thus, a widely-useful mimic of enzymes was discovered in plastic: Teflon-based Nafion, suspended (undisolved) in chloroform, or trifluoroethanol, caused novel, selective, cleavages of maytansinoid-precursor α-keto-acetals, even deprotections of chemically synthesized polypeptides normally requiring hydrogen fluoride, at neutral pH; i.e., super-acid chemistry without acid.

Invented Carbon-Carbon Bond Formation in Maytansinoid Synthesis, U. of Chicago

Carbon-Carbon bond-formation challenges synthetic chemists.  And linking carbons with multiple functional groups, even where carbon reactivities are favorable, often fails.  In a rapidly evolving synthesis of super-anticancer maytansinoids, linking a hydroxy-bearing carbon with an α-keto carbonyl would provide broad, easy access to their cyclic “dienone-carbinolamide” subunit -- a large, unstable, biologically-crucial, structure. But these carbons are unfavorably polarized; and both had multiple, closely spaced, unstable, functional groups.  The problem was solved by inventing:

(a) Novel carbonyl-reactivity-reversal employing, for the first time, nitroalkanes, in water, at pH 9 -- the carbonyl being expertly (see, above) derived from a highly unstable α-ketoacetal; the nitroalkane, from the alcohol.

(b) New reactions forming novel “dienone-carbinolamides” and, potentially, maytansinoids

Remediation via Continuous Heavy-metal-removal from Superfund Sites, Tulane

The novel removal of heavy metals from contaminated soil is an important goal in the field of environmental remediation.  Thus, the design & synthesis of amphiphilic molecules capable of continuously removing heavy metals from soil was proposed. This proposal gave rise to a large group-grant proposal with Tulane U. Chemical Engineers. The NIH funded this proposal, $100,000 per principal-investigator.

cis,cis-1,3,5-Trimethylcyclohexane-1,3,5-tricarboxylic Acid, PhD Thesis, MIT

Conceived to (a) model a novel acid-base behavior, (b) lead to atom-binding cage molecules, (c) arise from an adamantane precursor in one oxidative step, cis,cis-1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid proved far-more complicated, and richer, as it circularly spaced three, pH-fixed, converging carboxyl groups by ~0.25 nanometer, a positioning of atoms mesmerizing nanotechnologists, today.

Ultimately, a novel synthesis, from commercial 3,5,7-trimethyladamantan-1-ol, in four, tailored, selective, steps was uncovered:

(a) conversion of the adamantanol to its oxide;

(b) controlled thermolysis (photolysis) of the adamantoxide in benzene by slightly-more-than-3 equivalents of bromine to a bicyclic bromomethyl-dibromocyclohexanone;

 permanganate (chromic acid) oxidation of the bicyclocyclohexanone to a bicyclic lactone carboxylate; 

(d) ruthenium-tetroxide/periodate oxidation of the opened lactone to the crystalline triacid.

PH-driven triacid conformations were charted via 1H NMR and, crucially, in the Laboratory of Professor Jeremy Knowles, Harvard U., by special titrations, uncovering novel functional-group proximity effects behind conformations and pKa's.  (The triacid and its mono and dianions had carboxyl groups axial, (pKa)1 = 3.30, (pKa)2 = 5.85; the trianion had them equatorial, (pKa)3 = 7.30; the well-measured difference between (pKa)3 and (pKa)2 - very small compared to (pKa)2-(pKa)1 - revealing a conformational change shadowing trianion formation.)

Inter and intramolecular reactions of subnanometer-spaced functional groups, in triacid as well as novel cis,cis-1,3,5-trihydroxymethyl-1,3,5-trinitrocyclohexane frameworks, were also explored, creating, among others, poly-activated triacids, which have been very useful in controlled, serial derivatizations, enabling workers, internationally, to prepare numerous derivative-molecules, including "receptors", binding, occasionally manipulating, many species.
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