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Chemgenes Corporation

Sant K Srivastav

Suresh C Srivastava

Stanley J Szymanski, Jr

Alok Kumar Srivastava

Satya P Bajpai

Santhosh Kumar Thatikonda

Praveen K Shukla

Alok Srivastava

Santhosh K Thatikonda

This invention is related to nucleic acid chemistry and describes novel 1,2-dithiolane functionalized nucleoside phosphoramidites (1, Chart 1) and corresponding solid supports (2, Chart 1). In addition to these derivatives, 1,2-dithiolane moiety can also be functionalized to at the various positions of the nucleobase and sugar part as shown in Schemes 1 to 8. The nucleosides of our invention carry a primary hydroxyl for DMTr (4,4'-dimethoxytrityl) function for chain elongation. Furthermore, the phosphoramidite function is attached at the 3&#x2032;-hydroxyl of the nucleoside. This allows oligonucleotide chain extension under standard DNA and RNA synthesis chemistry conditions and techniques, thus leading to high quality oligonucleotides. These derivatives are useful for introduction of reactive thiol groups either at 3&#x2032;- or 5&#x2032;-end of the oligonucleotides on the solid supports such as gold, silver and quantum dots.

Dithiolane functionalized nucleoside amidites and supports for stronger immobilization of bio-molecules on solid surfaces

The present invention is directed to n-alkylated synthetic nucleosides of high regiospecific purity and oligonucleotides that can be utilized for studies on reversal of cytotoxic and mutagenic DNA damage, and as diagnostic tools.

Nucleosides and oligonucleotides for studies on reversal of cytotoxic and mutagenic damage of DNA and as diagnostics tools

The thiol modified oligonucleotides have vast number of applications in the field of nucleic acid chemistry. The conjugates generated by mono thiol groups are unstable at higher temperature, in high salt concentration buffers and in presence other thiols. There is strong need to develop a novel thiol modifier probes that can generate multiple thiol groups. Described herein are efficient processes and compounds, dithiolane phosphoramidites derivative and dithiolane succinyl supports. The advantage of our cyclic disulfide thiol modifier is multifold a) each incorporation introduces two thiol groups; b) it can be introduced at any desired site of oligonucleotides; c) The symmetrical branching nature of the spacer in the linker arm of dithiolane allows for clean oligo synthesis, where cleavage of the linker arm and thereby of loss of oligo chain is prevented. We have successfully made 20-mer oligonucleotide containing single dithiolane derivative at 3', and 21-mer oligonucleotides containing single dithiolane derivative at 5&#x2032; or in the middle of the mixed base sequence. HPLC and ESI MS analysis of these oligonucleotides indicated satisfactory purity and correct composition of these oligos, respectively.

Dithiolane based thiol modifier for labeling and stronger immobilization of bio-molecules on solid surfaces

This invention relates to n-alkylated synthetic nucleosides and phosphoramidites of high regio-specific purity and stability and for selective deprotection of the protecting group in oligonucleotides for the purpose of synthesis of high purity selectively n-alkylated sequence specific DNA and RNA. Such oligonucleotides are useful for study of mechanism of cytotoxic and mutagenic DNA damage, detection and reversal of cellular cytotoxic and mutagenic damages that occurs from the incorporation of methylated nucleosides, the corresponding phosphates and triphosphates and their precursors, via de novo DNA synthesis. The reagents could be extremely valuable tools as diagnostics and mutagenic reversal reagents. The present invention describes N-1-nitrogen alkylated purine and N-3 nitrogen alkylated pyrimidines with appropriate nucleobase amino protection, which are selectively deprotected with minimal migration of the alkyl substituent under the condition which are required for synthesizing high purity regiospecific N-1 and N-3 nitrogen alkylated oligonucleotides. A novel process has been developed to synthesize N-3 nitrogen alkylated cytidine.

Nucleosides and oligonucleotides for studies on reversal of cytotoxic and mutagenic damage of DNA potential diagnostics tools

The invention involves various embodiments of a method for treating a human being for a condition associated with (1) seizures, myoclonic seizures, epilepsy, refractory epilepsy, hyperkinetic movements or tremors of hands or feet, (2) a state of ataxia, (3) accumulation of neuronal autofluorescent storage bodies in lysosomes or neurons, or regression of motor development, and (4) low alertness, dementia or mental retardation. The method involves administering a therapeutically effective salt of N-6-trimethyl-L-lysine.

Method of treating a human being for a class of neurological defects and seizure disorders

The invention provides a method of synthesis of N-6-trimethyl-L-lysine (TML) derivative compounds for potential treatment of disorders resulting from deficiencies in the TML-carnitine pathway. The invention also provides a method of purification of TML and TML derivative compounds. The treatment of conditions of the diseases late infantile neuronal ceroid lipofuscinosis (LINCL) and neuronal ceroid lipofuscinosis (NCL) with TML were shown in the original parent application.

Method of synthesis and purification of N-6-trimethyl-L-lysine and derivative compounds

The invention involves various embodiments of a method for treating a human being for a condition associated with (1) a clinical state of impairment of carnitine or carnitine esters, or decreased fatty acid metabolism, (2) low energy production or lower ATP production, (3) clinical hyperammonemia, and (4) clinically high pyruvate levels resulting from a deficiency in the biosynthesis of carnitine. The method involves administering a therapeutically effective salt of N-6-trimethyl-L-lysine.

Method of treating a human being for a class of metabolic defects and energy production disorders

The invention provides compositions for and methods of treating a number of disorders. In one embodiment, the invention provides a method of treating a wide range of conditions by administering to a human being in need of such treatment, a therapeutically effective amount of (a) N-6-trimethyl-L-lysine of at least 98% purity, (b) a prodrug thereof, (c) an aliphatic chain derivative thereof, (d) an ester derivative thereof, (e) an amide derivative thereof, or (f) a pharmaceutically acceptable salt of said N-6-trimethyl-L-lysine or said prodrug.

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Burlington, MA, United States of America

Sant K Srivastav