Hypervalent Iodine-Mediated Synthesis of Steroidal 5/5-Spiroiminals.

The hypervalent iodine-mediated formation of steroidal 5/5-spiroiminals and 5/5-spiroaminals from steroidal amines is presented. Under the influence of excess PhI(OAc) and iodine in acetonitrile at 0 °C, steroidal amines smoothly underwent cyclization to give a mixture of 5/5-spiroiminals and 5/5-spiroaminals. This reaction represents the first example of a C-H-activation-mediated formation of a spiroiminal.

Effects of N7-Alkylguanine Conformation and Metal Cofactors on the Translesion Synthesis by Human DNA Polymerase η.

Non-enzymatic alkylation on DNA often generates N7-alkyl-2'-deoxyguanosine (N7alkylG) adducts as major lesions. N7alkylG adducts significantly block replicative DNA polymerases and can be bypassed by translesion synthesis (TLS) polymerases such as polymerase η (polη). To gain insights into the bypass of N7alkylG by TLS polymerases, we conducted kinetic and structural studies of polη catalyzing across N7BnG, a genotoxic lesion generated by the carcinogenic -nitrosobenzylmethylamine.

Translesion synthesis of the major nitrogen mustard-induced DNA lesion by human DNA polymerase η.

Nitrogen mustards are among the first modern anticancer chemotherapeutics that are still widely used as non-specific anticancer alkylating agents. While the mechanism of action of mustard drugs involves the generation of DNA interstrand cross-links, the predominant lesions produced by these drugs are nitrogen half-mustard-N7-dG (NHMG) adducts. The bulky major groove lesion NHMG, if left unrepaired, can be bypassed by translesion synthesis (TLS) DNA polymerases.

Photo-induced DNA interstrand cross-links formed by a coumarin-modified nucleoside.

Coumarins are a class of naturally occurring compounds that have been shown to form photochemical DNA interstrand cross-links (ICLs). However, study of a coumarin base has not been explored. Using nucleophilic substitution and phosphoramidite chemistry, we synthesized a coumarin base-containing oligonucleotide.

Synthesis and bioactivity of bis-steroidal pyrazine 23-deoxy-25-epi ritterostatin G1.

Cephalostatins, ritterazines and their hybrid bis-steroidal pyrazine analogs such as 25-epi-rittereostatin G1 show unusually high potency against a wide range of cancer cell lines. Herein, we report the synthesis and bioactivity of 23-deoxy-25-epi ritterostatin G1, which lacks the 23-hydroxyl group of 25-epi rittereostatin G1. The less oxygenated bis-steroidal pyrazine was ∼50- to 1000-fold less potent than 25-epi ritterostatin G1, highlighting the importance of the 23-hydroxyl group for the antiproliferative activity of the cephalostatin/ritterazine class of drugs.

Synthesis of 23-deoxy-25-epi north unit of cephalostatin 1 via reductive and oxidative modifications of hecogenin acetate.

An efficient synthesis of the 23-deoxy-25-epi north unit of cephalostatin 1 has been achieved in 17 steps via reductive and oxidative functionalizations of hecogenin acetate with an overall yield of 3.8%. This synthesis features transetherification-mediated E-ring opening, D-ring oxidation, hemiketalization-mediated E-ring closure, and stereoselective 5/5-spiroketalization.