Kohn K W, Orr A, O'Connor P M, Guziec L J, Guziec F S
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892.
J Med Chem. 1994 Jan 7;37(1):67-72. doi: 10.1021/jm00027a008.
The aim of this work was to identify nitrogen mustards that would react selectively with DNA, particularly in G-rich regions. A series of mono- and difunctional nitrogen mustards was synthesized in which the (2-chloroethyl)amino functions were connected to the N9 of 9-aminoacridine by way of a spacer chain consisting of two to six methylene units. The length of the spacer chain connecting the alkylating and putative DNA-intercalating groups was found to affect the preference for the alkylation of different guanine-N7 positions in a DNA sequence. All of the compounds reacted preferentially at G's that are followed by G as do most other types of nitrogen mustards, but the degree of selectivity was greater. The compounds reacted at much lower concentrations than were required for comparable reaction by mechlorethamine (HN2), consistent with initial noncovalent binding to DNA prior to guanine-N7 alkylation. The degree of DNA-sequence selectivity increased as the spacer-chain length decreased below four methylene units. Most strikingly, long spacer compounds reacted strongly at 5'-GT-3' sequences, whereas this reaction was almost completely suppressed when the spacer length was reduced to two or three methylenes. Mono- and difunctional compounds of a given spacer length showed no consistent difference in DNA-sequence preference.
这项工作的目的是鉴定能够与DNA发生选择性反应的氮芥，尤其是在富含鸟嘌呤的区域。合成了一系列单官能和双官能氮芥，其中（2-氯乙基）氨基官能团通过由两到六个亚甲基单元组成的间隔链连接到9-氨基吖啶的N9上。发现连接烷基化基团和假定的DNA嵌入基团的间隔链长度会影响DNA序列中不同鸟嘌呤-N7位置的烷基化偏好。所有这些化合物都优先在后面跟着鸟嘌呤的鸟嘌呤处发生反应，这与大多数其他类型的氮芥情况相同，但选择性程度更高。这些化合物在比氮芥（HN2）进行类似反应所需浓度低得多的情况下就能发生反应，这与在鸟嘌呤-N7烷基化之前先与DNA进行初始非共价结合一致。当间隔链长度减少到四个亚甲基单元以下时，DNA序列选择性程度增加。最引人注目的是，长间隔链化合物在5'-GT-3'序列处反应强烈，而当间隔链长度减少到两个或三个亚甲基时，这种反应几乎完全受到抑制。给定间隔链长度的单官能和双官能化合物在DNA序列偏好上没有一致的差异。
